european union risk management plan (eu-rmp) …...completed clinical trial programme 14 may2018 5.3...

EPREX (Epoetin Alfa)Risk Management Plan Version 5.4

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European Union Risk Management Plan (EU-RMP)EPREX® (epoetin alfa)

Active substance(s)(INN or common name):

Epoetin alfa

Pharmaco-therapeutic group(ATC Code):

Other antianemic preparationsB03XA01

Name of Marketing Authorisation Holderor Applicant:

Janssen-Cilag Pharma GmbH, AustriaJANSSEN-CILAG GmbH, GermanyJanssen-Cilag NV, BelgiumJohnson & Johnson, Prodaja medicinskih in farmacevtskih

izdelkov, d.o.o., BulgariaJanssen-Cilag International NV, CyprusJanssen-Cilag s.r.o., Czech RepublicJanssen-Cilag A/S, DenmarkJanssen-Cilag OY, FinlandJANSSEN-CILAG, FranceJanssen-Cilag Pharmaceutical S.A.C.I., GreeceJanssen-Cilag LimitedJanssen-Cilag SpA, ItalyJanssen-Cilag, NV, LuxembourgJanssen-Cilag International NV, MaltaJanssen-Cilag BV, NetherlandsJanssen-Cilag AS, NorwayJanssen-Cilag Farmaceutica, Lda, PortugalJanssen-Cilag S.A.Johnson & Johnson, Prodaja medicinskih in farmacevtskih

izdelkov, d.o.o., BulgariaJanssen-Cilag S.A., SpainJanssen-Cilag AB, SwedenJanssen-Cilag Ltd, United Kingdom

Number of medicinal productsto which this RMP refers:

1

Product(s) concerned(brand names):

EPREXERYPOERYPO FS

Data lock point for current RMP 20 December 2017 Version number 5.4

Date of final sign off 19 June 2018

Issue Date: 19 June 2018Version No: 5.4Supersedes Version: 5.3Document No.: EDMS-ERI-13292852:1.0

Confidentiality StatementThe information in this document contains trade secrets and commercial information that are privileged or confidential and may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by them. These restrictions on disclosure will apply equally to all future information supplied to you, which is indicated as privileged or confidential.


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TABLE OF CONTENTS

TABLE OF CONTENTS ............................................................................................................................... 2

PART I: PRODUCT(S) OVERVIEW ............................................................................................................. 4Overview of Versions: ................................................................................................................................... 7Current RMP Versions Under Evaluation: .................................................................................................... 7RMP Version 5.2 – submitted 30 MAR 2018 – FR/H/003/09-10,13-14/II/132/G................................................... 7

PART II: SAFETY SPECIFICATION .......................................................................................................... 18

MODULE SI: EPIDEMIOLOGY OF THE INDICATION(S) AND TARGET POPULATION ....................... 18Indication ..................................................................................................................................................... 19SI.1. Epidemiology of the Disease ......................................................................................................... 20SI.2. Concomitant Medication(s) in the Target Population..................................................................... 32SI.3. Important Comorbidities Found in the Target Population .............................................................. 35

MODULE SII: NONCLINICAL PART OF THE SAFETY SPECIFICATION............................................... 52SII. Conclusions on Nonclinical Data ................................................................................................... 57

MODULE SIII: CLINICAL TRIAL EXPOSURE .......................................................................................... 58SIII.1. Brief Overview of Development ..................................................................................................... 59SIII.2. Clinical Trial Exposure ................................................................................................................... 61

MODULE SIV: POPULATIONS NOT STUDIED IN CLINICAL TRIALS ................................................. 104SIV.1. Limitations of Adverse Drug Reaction Detection Common to All Clinical Trial

Development Programmes .......................................................................................................... 105SIV.2. Effect of Exclusion Criteria in the Clinical Trial Development Plan.............................................. 107SIV.3. Limitations in Respect to Populations Typically Under-represented in Clinical Trial

Development Programme(s) ........................................................................................................ 110SIV.4. Conclusions on the Populations Not Studied and Other Limitations of the Clinical Trial

Development Programme ............................................................................................................ 112

MODULE SV: POSTAUTHORISATION EXPERIENCE .......................................................................... 113SV.1. Action Taken by Regulatory Authorities and/or Marketing Authorisation Holders for Safety

Reasons ....................................................................................................................................... 114SV.2. Nonstudy Postauthorisation Exposure......................................................................................... 124SV.2.1. Method used to Calculate Exposure......................................................................................... 124SV.2.2. Exposure................................................................................................................................... 124SV.3. Postauthorisation Use in Populations Not Studied in Clinical Trials ............................................ 127SV.4. Postauthorisation Off-label Use ................................................................................................... 127SV.5. Epidemiologic Study Exposure .................................................................................................... 127

MODULE SVI: ADDITIONAL EU REQUIREMENTS FOR THE SAFETY SPECIFICATION.................. 130SVI.1. Potential for Harm From Overdose .............................................................................................. 131SVI.2. Potential for Transmission of Infectious Agents........................................................................... 131SVI.3. Potential for Misuse for Illegal Purposes...................................................................................... 131SVI.4. Potential for Medication Errors..................................................................................................... 131SVI.4.1. Description of Medication Errors During the Clinical Trial Programme .................................... 131SVI.4.2. Preventive Measures for the Final Product(s) Being Marketed................................................ 132SVI.4.3. Effect of Device Failure............................................................................................................. 133SVI.4.4. Reports of Medication Errors with the Marketed Product(s)..................................................... 133SVI.5. Potential for Off-label Use............................................................................................................ 137SVI.6. Specific Paediatric Issues ............................................................................................................ 137SVI.6.1. Issues Identified in Paediatric Investigation Plans ................................................................... 137SVI.6.2. Potential for Paediatric Off-label Use ....................................................................................... 138SVI.7. Conclusions.................................................................................................................................. 138


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MODULE SVII: IDENTIFIED AND POTENTIAL RISKS .......................................................................... 139SVII.1. Newly Identified Safety Concerns (since this module was last submitted).................................. 140SVII.2. Recent Study Reports With Implications for Safety Concerns..................................................... 140SVII.3. Details of Important Identified and Potential Risks From Clinical Development and

Postauthorisation Experience (including newly identified)........................................................... 140SVII.4. Identified and Potential Interactions............................................................................................. 194SVII.4.1. Overview of Potential for Interactions....................................................................................... 194SVII.4.2. Important Identified and Potential Interactions ......................................................................... 195SVII.5. Pharmacologic Class Effects ....................................................................................................... 195SVII.5.1. Pharmacologic Class Risks Already Included as Important Identified or Potential Risks ........ 196SVII.5.2. Important Pharmacologic Class Effects That Are NOT Considered to be Important

Identified or Potential Risks ...................................................................................................... 199

MODULE SVIII: SUMMARY OF THE SAFETY CONCERNS.................................................................. 200

PART III: PHARMACOVIGILANCE PLAN .............................................................................................. 202III.1. Safety Concerns and Overview of Planned Pharmacovigilance Actions..................................... 203III.2. Additional Pharmacovigilance Activities to Assess the Effectiveness of Risk Minimisation

Measures ..................................................................................................................................... 204III.3. Studies and Other Activities Completed Since the Last Update of the Pharmacovigilance

Plan .............................................................................................................................................. 204III.4. Details of Outstanding Additional Pharmacovigilance Activities .................................................. 205III.4.1. Imposed Mandatory Additional Pharmacovigilance Activity (Key to Benefit-Risk)................... 205III.4.2. Mandatory Additional Pharmacovigilance Activity (Being a Specific Obligation) ..................... 205III.4.3. Required Additional Pharmacovigilance Activities to Address Specific Safety Concerns

or to Measure Effectiveness of Risk Minimisation Measures ................................................... 205III.4.4. Stated Additional Pharmacovigilance Activities........................................................................ 205III.5. Summary of the Pharmacovigilance Plan .................................................................................... 206III.5.1. Table of Ongoing and Planned Additional Pharmacovigilance Studies/Activities in the

Pharmacovigilance Plan ........................................................................................................... 206III.5.2. Table of Completed Studies/Activities From the Pharmacovigilance Plan............................... 207

PART IV: PLANS FOR POSTAUTHORISATION EFFICACY STUDIES ................................................ 208IV.1 Applicability of Efficacy to All Patients in the Target Population .................................................. 209IV.2. Tables of Postauthorisation Efficacy Studies............................................................................... 209IV.3. Summary of the Postauthorisation Efficacy Development Plan................................................... 209IV.4. Summary of Completed Postauthorisation Efficacy Studies........................................................ 209

PART V: RISK MINIMISATION MEASURES .......................................................................................... 210V.1. Risk Minimisation Measures by Safety Concern ......................................................................... 211V.2. Risk Minimisation Measure Failure .............................................................................................. 217V.3. Summary Table of Risk Minimisation Measures.......................................................................... 217

PART VI: SUMMARY OF ACTIVITIES IN THE RISK MANAGEMENT PLAN BY PRODUCT .............. 219VI.1. Elements for Summary Tables in the EPAR................................................................................ 220VI.1.1. Summary Table of Safety Concerns......................................................................................... 220VI.1.2. Table of Ongoing and Planned Additional Pharmacovigilance Studies/Activities in the

Pharmacovigilance Plan ........................................................................................................... 220VI.1.3. Summary of Postauthorisation Efficacy Development Plan ..................................................... 220VI.1.4. Summary Table of Risk Minimisation Measures ...................................................................... 221VI.2. Elements for a Public Summary................................................................................................... 222VI.2.1. Overview of Disease Epidemiology .......................................................................................... 223VI.2.2. Summary of Treatment Benefits ............................................................................................... 223VI.2.3. Unknowns Relating to Treatment Benefits ............................................................................... 223VI.2.4. Summary of Safety Concerns................................................................................................... 224VI.2.5 Summary of Additional Risk Minimisation Measures by Safety Concern................................. 225VI.2.6 Planned Postauthorisation Development Plan ......................................................................... 226VI.2.7 Summary of Changes to the Risk Management Plan Over Time............................................. 227


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European Union Risk Management Plan (EU-RMP)EPREX (epoetin alfa)

PART I: PRODUCT(S) OVERVIEW

Active substance(s)(INN or common name):

Epoetin alfa

Pharmaco-therapeutic group(ATC Code):

Other antianemic preparationsB03XA01

Name of Marketing Authorisation Holderor Applicant:

Janssen-Cilag Pharma GmbH, AustriaJANSSEN-CILAG GmbH, GermanyJanssen-Cilag NV, BelgiumJohnson & Johnson, Prodaja medicinskih in farmacevtskih

izdelkov, d.o.o., BulgariaJanssen-Cilag International NV, CyprusJanssen-Cilag s.r.o., Czech RepublicJanssen-Cilag A/S, DenmarkJanssen-Cilag OY, FinlandJANSSEN-CILAG, FranceJanssen-Cilag Pharmaceutical S.A.C.I., GreeceJanssen-Cilag LimitedJanssen-Cilag SpA, ItalyJanssen-Cilag, NV, LuxembourgJanssen-Cilag International NV, MaltaJanssen-Cilag BV, NetherlandsJanssen-Cilag AS, NorwayJanssen-Cilag Farmaceutica, Lda, PortugalJanssen-Cilag S.A.Johnson & Johnson, Prodaja medicinskih in farmacevtskih

izdelkov, d.o.o., BulgariaJanssen-Cilag S.A., SpainJanssen-Cilag AB, SwedenJanssen-Cilag Ltd, United Kingdom

Number of medicinal productsto which this RMP refers:

1

Product(s) concerned(brand names):

EPREXERYPOERYPO FS

Data lock point for current RMP 20 December 2017 Version number 5.4

Date of final sign off 19 June 2018




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PRODUCTS OVERVIEW

Administrative Information on the RMP

PART MODULE/ANNEX

Date when the module or part was last submitted

(final sign off date)

Version number of RMP

when last submitted1

PART II Safety Specification

SI Epidemiology of the Indication and Target Population(s)

14 May 2018 5.3

SII Nonclinical Part of the Safety Specification

14 May 2018 5.3

SIII Clinical Trial Exposure 14 May 2018 5.3

SIV Populations Not Studied in Clinical Trials

14 May 2018 5.3

SV Postauthorisation Experience 14 May 2018 5.3

SVI Additional EU Requirements for the Safety Specification

14 May 2018 5.3

SVII Identified and Potential Risks 14 May 2018 5.3

SVIII Summary of the Safety Concerns 14 May 2018 5.3

PART III Pharmacovigilance Plan 14 May 2018 5.3

PART IV Plan for Postauthorisation Efficacy Trials 14 May 2018 5.3

PART V Risk Minimisation Measures 14 May 2018 5.3

PART VI Summary of the RMP 14 May 2018 5.3

PART VII Annexes 5.3

ANNEX 1 Eudravigilance Interface Not applicable --

ANNEX 2 SmPC and Package Leaflet 14 May 2018 5.3

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Version 5.2 was submitted on March 30, 2018 within procedure FR/H/003/09-10,13-14/II/132/G and is therefore the most recently submitted version. However, RMP version 5.3 (current) supersedes version 5.1 as base document within procedure FR/H/003/09-10,13-14/II/129.


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PRODUCTS OVERVIEW

Administrative Information on the RMP

PART MODULE/ANNEX

Date when the module or part was last submitted

(final sign off date)

Version number of RMP

when last submitted1

ANNEX 3 Worldwide Marketing Authorisation Status by Country (including EEA)

14 May 2018 5.3

ANNEX 4 Synopsis of the Ongoing and Completed Clinical Trial Programme

14 May 2018 5.3

ANNEX 5 Synopsis of the Ongoing and Completed Pharmacoepidemiological Study Programme

Not applicable --

ANNEX 6 Protocols for Proposed and Ongoing Trials/Studies in Categories 1-3

14 May 2018 5.3

ANNEX 7 Specific Adverse Event Follow-up Forms

Not applicable --

ANNEX 8 Protocols for Proposed and Ongoing Studies in RMP Part IV

Not applicable --

ANNEX 9 Synopsis of Newly Available Study Reports for RMP Parts III-IV

14 May 2018 5.3

ANNEX 10 Details of Proposed Additional Risk Minimisation Activities

Not applicable --

ANNEX 11 Mock up of Proposed Additional Risk Minimisation Measures

Not applicable --

ANNEX 12 Other Supporting Data 14 May 2018 5.3

QPPV Name(s): PharmD, Ph.D

QPPV Signature: Electronic signature appended at the end of this document

Contact person for this RMP: DVM, PhDEMEA Regulatory Affairs Liaison Established Products, Global Regulatory Affairs

E-mail address or telephone number of contact person:


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Overview of Versions:

Version number of last agreed RMP:

Version number 5.0

Agreed withinMutual Recognition Procedure FR/H/003/09-10,13-14/II/124

Current RMP Versions Under Evaluation:

RMP Version 5.2 – submitted 30 MAR 2018 – FR/H/003/09-10,13-14/II/132/G


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Invented name(s) of the medicinal product in the European Economic Area (EEA)

EPREX®/ERYPO®

Authorisation procedure Mutual Recognition and National

Brief description of product including

Chemical class

Summary of mode of action

Important information about its composition (eg, origin of active substance of biologicals, relevant adjuvants or residues for vaccines)

Erythropoietin is a mitosis-stimulating factor and differentiating hormone, which stimulates erythropoiesis. Epoetin alfa is produced in Chinese hamster ovary cells by recombinant DNA technology and cannot be distinguished from human erythropoietin with regard to its biological properties. The efficacy of epoetin alfa has been demonstrated in humans in clinical trials and postauthorisation use. After administration of epoetin alfa, the number of erythrocytes, haemoglobin (HGB) values, reticulocyte counts, and the iron-incorporation rate increase.

Indication(s) in the EEA

Current Chronic Renal Failure

EPREX, ERYPO is indicated for the treatment of symptomatic anaemia associated with chronic renal failure (CRF):

In adults and paediatrics aged 1 to 18 years on haemodialysis and adult patients on peritoneal dialysis.

In adults with renal insufficiency not yet undergoing dialysis for the treatment of severe anaemia of renal origin accompanied by clinical symptoms in patients.

Cancer

EPREX, ERYPO is indicated in adults receiving chemotherapy for solid tumours, malignant lymphoma or multiple myeloma, and at risk of transfusion as assessed by the patient’s general status (eg, cardiovascular status, pre-existing anaemia at the start of chemotherapy) for the treatment of anaemia and reduction of transfusion requirements.

Autologous Blood Donation

EPREX/ERYPO is indicated in adults in a predonation programme to increase the yield of autologous blood.Treatment should only be given to patients with moderate anaemia (HGB concentration range between 10 to 13 g/dL [6.2 to 8.1 mmol/L], no iron deficiency) if blood-saving procedures are not available or insufficient when the scheduled major elective surgery requires a large volume of blood (4 or more units of blood for females or 5 or more units for males).


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Surgery

EPREX, ERYPO is indicated for non-iron deficient adults prior to major elective orthopaedic surgery, having a high perceived risk for transfusion complications to reduce exposure to allogeneic blood transfusions. Use should be restricted to patients with moderate anaemia (eg, HGB concentration range between 10 to 13 g/dL) who do not have an autologous predonation programme available and with expected moderate blood loss (900 to 1,800 mL).

Treatment of adult patients with low- or intermediate-1-risk myelodysplastic syndromes

EPREX, ERYPO is indicated for the treatment of anaemia (HGB concentration of ≤10 g/dL) in adults with low- or intermediate-1-risk myelodysplastic syndromes (MDS).

Proposed None.

Posology and route of administration in the EEA

Current Treatment of symptomatic anaemia in adult chronic renal failure patients:

Anaemia symptoms and sequelae may vary with age, gender, and comorbid medical conditions; a physician’s evaluation of the individual patient’s clinical course and condition is necessary.

The recommended desired HGB concentration range is between 10 g/dL to 12 g/dL (6.2 to 7.5 mmol/L). EPREX, ERYPO should be administered in order to increase HGB to not greater than 12 g/dL (7.5 mmol/L). A rise in HGB of greater than 2 g/dL (1.25 mmol/L) over a 4-week period should be avoided. If it occurs, appropriate dose adjustment should be made asprovided.

Due to intra-patient variability, occasional individual HGB values for a patient above and below the desired HGB concentration range may be observed. Haemoglobin variability should be addressed through dose management, with consideration for the HGBconcentration range of 10g/dL (6.2 mmol/L) to 12g/dL(7.5 mmol/L).

A sustained HGB level of greater than 12g/dL(7.5 mmol/L) should be avoided. If the HGB is rising by more than 2 g/dL (1.25 mmol/L) per month, or if the sustained HGB exceeds 12g/dL (7.5 mmol/L), reduce the EPREX, ERYPO dose by 25%. If the HGB exceeds


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13 g/dL (8.1 mmol/L), discontinue therapy until it falls below 12 g/dL (7.5 mmol/L) and then reinstitute EPREX, ERYPO therapy at a dose 25% below the previous dose.

Patients should be monitored closely to ensure that the lowest approved effective dose of EPREX, ERYPO is used to provide adequate control of anaemia and of the symptoms of anaemia, whilst maintaining a HGBconcentration below or at 12 g/dL (7.5 mmol/L).

Caution should be exercised with escalation of erythropoiesis-stimulating agent (ESA) doses in patients with CRF. In patients with a poor HGB response to ESA, alternative explanations for the poor response should be considered.

Treatment with EPREX, ERYPO is divided into 2 stages – correction and maintenance phase.

Adult haemodialysis patients

In patients on haemodialysis where intravenous (IV) access is readily available, administration by the IVroute is preferable.

Correction phase:

The starting dose is 50 international units (IU)/kg, 3 times per week.

If necessary, increase or decrease the dose by 25 IU/kg (3 times per week) until the desired HGBconcentration range between 10 g/dL to 12 g/dL(6.2 to 7.5 mmol/L) is achieved (this should be done in steps of at least 4 weeks).

Maintenance phase:

The recommended total weekly dose is between 75 IU/kg and 300 IU/kg.

Appropriate adjustment of the dose should be made in order to maintain HGB values within the desired concentration range between 10 g/dL to 12 g/dL(6.2 to 7.5 mmol/L).

Patients with very low initial HGB (<6 g/dL or <3.75 mmol/L) may require higher maintenance doses than patients whose initial anaemia is less severe (>8 g/dL or >5 mmol/L).

Adult patients with renal insufficiency not yet undergoing dialysis

Where IV access is not readily available EPREX, ERYPO may be administered subcutaneously.

Correction phase:

Starting dose of 50 IU/kg, 3 times per week, followed if necessary by a dosage increase with


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25 IU/kg increments (3 times per week) until the desired goal is achieved (this should be done in steps of at least 4 weeks).

Maintenance phase:

During the maintenance phase, EPREX, ERYPO can be administered either 3 times per week, and in the case of subcutaneous (SC) administration, once weekly or once every 2 weeks.

Appropriate adjustment of dose and dose intervals should be made in order to maintain HGB values at the desired level: HGB between 10 g/dL and 12 g/dL(6.2 to 7.5 mmol/L). Extending dose intervals may require an increase in dose.

The maximum dosage should not exceed 150 IU/kg 3 times per week, 240 IU/kg (up to a maximum of 20,000 IU) once weekly, or 480 IU/kg (up to a maximum of 40,000 IU), once every 2 weeks.

Adult peritoneal dialysis patients

Where IV access is not readily available, EPREX,ERYPO may be administered subcutaneously.

Correction phase:

The starting dose is 50 IU/kg, 2 times per week.

Maintenance phase:

The recommended maintenance dose is between 25 IU/kg and 50 IU/kg, 2 times per week in 2 equal injections.

Appropriate adjustment of the dose should be made in order to maintain HGB values at the desired level between 10 g/dL to 12 g/dL (6.2 to 7.5 mmol/L).

Treatment of adult patients with chemotherapy-induced anaemia:

Anaemia symptoms and sequelae may vary with age, gender, and overall burden of disease; a physician’s evaluation of the individual patient’s clinical course and condition is necessary.

EPREX, ERYPO should be administered to patients with anaemia (eg, HGB concentration ≤10 g/dL[6.2 mmol/L]).

The initial dose is 150 IU/kg subcutaneously, 3 times per week.

Alternatively, EPREX, ERYPO can be administered at an initial dose of 450 IU/kg subcutaneously once weekly.

Appropriate adjustment of the dose should be made in order to maintain HGB concentrations within the


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desired concentration range between 10 g/dL to 12 g/dL(6.2 to 7.5 mmol/L).

Due to intra-patient variability, occasional individual HGB concentrations for a patient above and below the desired HGB concentration range may be observed. Haemoglobin variability should be addressed through dose management, with consideration for the desired HGB concentration range between 10g/dL(6.2 mmol/L) to 12g/dL (7.5 mmol/L). A sustained HGB concentration of greater than 12g/dL(7.5 mmol/L) should be avoided; guidance for appropriate dose adjustment for when HGBconcentrations exceed 12g/dL (7.5 mmol/L) is described below.

If the HGB concentration has increased by at least 1 g/dL (0.62 mmol/L) or the reticulocyte count has increased ≥ 40,000 cells/µL above baseline after 4 weeks of treatment, the dose should remain at 150 IU/kg 3 times per week or 450 IU/kg once weekly(QW).

If the HGB concentration increase is <1 g/dL(<0.62 mmol/L) and the reticulocyte count has increased <40,000 cells/µL above baseline, increase the dose to 300 IU/kg 3 times per week. If after an additional 4 weeks of therapy at 300 IU/kg 3 times per week the HGB concentration has increased ≥1 g/dL(≥0.62 mmol/L) or the reticulocyte count has increased ≥40,000 cells/µL, the dose should remain at 300 IU/kg 3 times per week.

If the HGB concentration has increased <1 g/dL(<0.62 mmol/L) and the reticulocyte count has increased <40,000 cells/µL above baseline, response is unlikely and treatment should be discontinued.

Dose adjustment to maintain HGB concentrations between 10 g/dL to 12 g/dL

If the HGB concentration is increasing by more than 2 g/dL (1.25 mmol/L) per month, or if the HGBconcentration level exceeds 12 g/dL (7.5 mmol/L), reduce the EPREX, ERYPO dose by about 25% to 50%.

If the HGB concentration exceeds 13 g/dL(8.1 mmol/L), discontinue therapy until it falls below 12 g/dL (7.5 mmol/L) and then reinstitute EPREX, ERYPO therapy at a dose 25% below the previous dose.

Patients should be monitored closely to ensure that the lowest approved dose of ESA is used to provide adequate control of the symptoms of anaemia.

EPREX, ERYPO therapy should continue until 1 month after the end of chemotherapy.


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Treatment of adult surgery patients in an autologous blood donation programme:

Mildly anaemic patients (haematocrit [HCT] of 33% to 39%) requiring predeposit of ≥4 units of blood should be treated with EPREX, ERYPO 600 IU/kgintravenously, 2 times per week for 3 weeks prior to surgery. EPREX, ERYPO should be administered after the completion of the blood donation procedure.

Treatment of adult patients scheduled for major elective orthopaedic surgery:

The recommended dose is EPREX, ERYPO 600 IU/kgadministered subcutaneously weekly for 3 weeks (Days -21, -14, and -7) prior to surgery and on the day of surgery.

In cases where there is a medical need to shorten the lead time before surgery to less than 3 weeks, EPREX, ERYPO 300 IU/kg should be administered subcutaneously daily for 10 consecutive days prior to surgery, on the day of surgery, and for 4 days immediately thereafter.

If the HGB level reaches 15 g/dL, or higher, during the perioperative period, administration of EPREX, ERYPO should be stopped and further dosages should not be administered.

Paediatric population

Treatment of symptomatic anaemia in chronic renal failure patients on haemodialysis

Anaemia symptoms and sequelae may vary with age, gender, and comorbid medical conditions; a physician’s evaluation of the individual patient’s clinical course and condition is necessary.

In paediatric patients, the recommended HGB concentration range is between 9.5 g/dL to 11 g/dL (5.9 to 6.8 mmol/L). EPREX, ERYPO should be administered in order to increase HGB to not greaterthan 11 g/dL (6.8 mmol/L). A rise in HGB of greater than 2 g/dL (1.25 mmol/L) over a 4-week period should be avoided. If it occurs, appropriate dose adjustment should be made as provided.

Patients should be monitored closely to ensure that the lowest approved dose of EPREX, ERYPO is used to provide adequate control of anaemia and of the symptoms of anaemia.

Treatment with EPREX, ERYPO is divided into 2 stages – correction and maintenance phase.

In paediatric patients on haemodialysis where IV access is readily available, administration by the IV route is


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preferable.

Correction phase:

The starting dose is 50 IU/kg, intravenously, 3 times per week.

If necessary, increase or decrease the dose by 25 IU/kg (3 times per week) until the desired HGB concentration range of between 9.5 g/dL to 11 g/dL (5.9 to 6.8 mmol/L) is achieved (this should be done in steps of at least 4 weeks).

Maintenance phase:

Appropriate adjustment of the dose should be made in order to maintain HGB levels within the desired concentration range between 9.5 g/dL to 11 g/dL (5.9 to 6.8 mmol/L).

Generally, children under 30 kg require higher maintenance doses than children over 30 kg and adults. Paediatric patients with very low initial HGB (<6.8 g/dL or <4.25 mmol/L) may require higher maintenance doses than patients whose initial HGB is higher (>6.8 g/dL or >4.25 mmol/L).

Treatment of paediatric patients with chemotherapy-induced anaemia

The safety and efficacy of EPREX, ERYPO in paediatric patients receiving chemotherapy have not been established

Treatment of paediatric surgery patients in an autologous predonation programme

The safety and efficacy of EPREX, ERYPO in paediatrics have not been established. No data are available.

Treatment of paediatric patients scheduled for major elective orthopaedic surgery

The safety and efficacy of EPREX, ERYPO in paediatrics have not been established. No data are available.

Method of administration

Precautions to be taken before handling or administering the medicinal product

Before use, leave the EPREX, ERYPO syringe to stand until it reaches room temperature. This usually takes between 15 and 30 minutes.


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Treatment of symptomatic anaemia in adult chronic renal failure patients

In patients with CRF where IV access is routinely available (haemodialysis patients), administration of EPREX, ERYPO by the IV route is preferable.

Where IV access is not readily available (patients not yet undergoing dialysis and peritoneal dialysis patients), EPREX, ERYPO may be administered as a SC injection.

Treatment of adult patients with chemotherapy-induced anaemia

EPREX, ERYPO should be administered as a SC injection.

Treatment of adult surgery patients in an autologous predonation programme

EPREX, ERYPO should be administered by the IV route.

Treatment of adult patients scheduled for major elective orthopaedic surgery


Treatment of symptomatic anaemia in paediatric chronic renal failure patients on haemodialysis

In paediatric patients with CRF where IV access is routinely available (haemodialysis patients), administration of EPREX, ERYPO by the IV route is preferable.

Intravenous administration

Administer over at least 1 to 5 minutes, depending on the total dose. In haemodialysed patients, a bolus injection may be given during the dialysis session through a suitable venous port in the dialysis line. Alternatively, the injection can be given at the end of the dialysis session via the fistula needle tubing, followed by 10 mL of isotonic saline to rinse the tubing and ensure satisfactory injection of the product into the circulation.

A slower administration is preferable in patients who react to the treatment with “flu-like” symptoms.

Do not administer EPREX, ERYPO by IV infusion or in conjunction with other drug solutions.

Subcutaneous administration

A maximum volume of 1 mL at 1 injection site should generally not be exceeded. In case of larger volumes, more than 1 site should be chosen for the injection.


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The injections should be given in the limbs or the anterior abdominal wall.

In those situations in which the physician determinesthat a patient or caregiver can safely and effectively administer EPREX, ERYPO subcutaneously themselves, instruction as to the proper dosage and administration should be provided.

As with any injectable product, check that there are no particles in the solution or change in colour.

Treatment of adult patients with low- or intermediate-1-risk MDS

EPREX, ERYPO should be administered to patients with anaemia (eg, HGB concentration 10 g/dL [6.2 mmol/L]).

The recommended starting dose is EPREX, ERYPO 450 IU/kg (maximum total dose is 40,000 IU) administered subcutaneously once every week.

It is recommended that response be assessed at Week 8. If no erythroid response is achieved after 8 weeks according to International Working Group 2006 criteria, and the HGB concentration is below 11 g/dL (6.8 mmol/L), the dose should be increased from 450 IU/kg once every week to 1,050 IU/kg once every week (maximum dose is 80,000 IU per week).

Appropriate dose adjustments should be made to maintain HGB concentrations within the target range of 10 g/dL to 12 g/dL (6.2 to 7.5 mmol/L). Epoetin alfa should be withheld or the dose reduced when the HGB concentration exceeds 12 g/dL (7.5 mmol/L). Upon dose reduction, if HGB concentration drops 1 g/dL, the dose should be increased.

A sustained HGB concentration of greater than 12 g/dL (7.5 mmol/L) should be avoided.


Proposed None

Pharmaceutical form(s) and strength(s)

Current Clear, colourless solution for injection in prefilledsyringe in the following strengths: 2,000 IU/mL, 4,000 IU/mL, 10,000 IU/mL, and 40,000/mL.

EPREX is available in the following prefilled syringevolumes: 1,000 IU in 0.5 mL, 2,000 IU in 0.5 mL,


17

3,000 IU in 0.3 mL, 4,000 IU in 0.4 mL, 5,000 IU in 0.5 mL, 6,000 IU in 0.6 mL, 8,000 IU in 0.8 mL, 10,000 IU in 1.0 mL, 20,000 IU in 0.5 mL, 30,000 IU in 0.75 mL, and 40,000 IU in 1.0 mL.

Country and date of first authorisation worldwide Switzerland 27 July 1988

Country and date of first launch worldwide Portugal,Malta

November 1988

Country and date of first authorisation in the EEA France 4 August 1988

Is the product subject of additional monitoring in the EU? Yes No


18


PART II: SAFETY SPECIFICATION

Module SI: Epidemiology of the Indication(s) and Target Population

Active substance Epoetin alfa

Product(s) concerned EPREXERYPOERYPO FS

MAH/MAA name Janssen-Cilag Pharma GmbH, AustriaJANSSEN-CILAG GmbH, GermanyJanssen-Cilag NV, BelgiumJohnson & Johnson, Prodaja medicinskih in farmacevtskih izdelkov,

d.o.o., BulgariaJanssen-Cilag International NV, CyprusJanssen-Cilag s.r.o., Czech RepublicJanssen-Cilag A/S, DenmarkJanssen-Cilag OY, FinlandJANSSEN-CILAG, FranceJanssen-Cilag Pharmaceutical S.A.C.I., GreeceJanssen-Cilag LimitedJanssen-Cilag SpA, ItalyJanssen-Cilag, NV, LuxembourgJanssen-Cilag International NV, MaltaJanssen-Cilag BV, NetherlandsJanssen-Cilag AS, NorwayJanssen-Cilag Farmaceutica, Lda, PortugalJanssen-Cilag S.A.Johnson & Johnson, Prodaja medicinskih in farmacevtskih izdelkov,

d.o.o., BulgariaJanssen-Cilag S.A., SpainJanssen-Cilag AB, SwedenJanssen-Cilag Ltd, United Kingdom

Data lock point for this module 20 December 2017

Version number of RMP when this module was last updated 5.1




19

Indication

EPREX, ERYPO (epoetin alfa) is indicated in the European Union (EU)

For the treatment of symptomatic anaemia associated with CRF

In adults and paediatrics aged 1 to 18 years on haemodialysis and adult patients on peritoneal dialysis.

In adults with renal insufficiency not yet undergoing dialysis for the treatment of severe anaemia of renal origin accompanied by clinical symptoms in patients.

In adults receiving chemotherapy for solid tumours, malignant lymphoma or multiple myeloma, and at risk of transfusion as assessed by the patient’s general status (eg, cardiovascular status, pre-existing anaemia at the start of chemotherapy) for the treatment of anaemia and reduction of transfusion requirements.

In adults in a predonation programme to increase the yield of autologous blood. Treatment should only be given to patients with moderate anaemia (HGB concentration range between10 to 13 g/dL [6.2 to 8.1 mmol/L], no iron deficiency) if blood-saving procedures are not available or insufficient when the scheduled major elective surgery requires a large volume of blood (4 or more units of blood for females or 5 or more units for males).

For non-iron-deficient adults prior to major elective orthopaedic surgery, having a high perceived risk for transfusion complications to reduce exposure to allogeneic blood transfusions. Use should be restricted to patients with moderate anaemia (eg, HGB concentration range between 10 to 13 g/dL [6.2 to 8.1 mmol/L]) who do not have an autologous predonation programme available and with expected moderate blood loss (900 to 1,800 mL).

The current EPREX Summary of Product Characteristics (SmPC) was approved by L’Agence

Nationale de Sécurité du Médicament et des Produits de Santé (ANSM) in her capacity as the

Reference Member State in the Mutual Recognition Procedure in July 2015 and the information

in this document reflects the current labelling.

In addition to the current indications as noted above, an indication for the treatment of adult

patients with low- or intermediate-1-risk MDS has been proposed and approved: EPREX,

ERYPO is indicated for the treatment of anaemia (HGB concentration of 10 g/dL) in adults

with low- or intermediate-1-risk MDS.

Of note, the term “Surgery” used throughout this document relates to the indication associated

with the treatment of non-iron-deficient adults prior to major elective orthopaedic surgery.

This risk management plan (RMP) includes safety data from patients receiving EPREX as well

as relevant safety data for other ESAs including PROCRIT®, where appropriate, to provide a

comprehensive characterisation of identified and potential safety risks.


20

SI.1. Epidemiology of the Disease

Chronic Renal Failure

Incidence and Prevalence

Adults

The National Health Service (NHS) in the United Kingdom provided annual data on primary

care activity through the Quality and Outcomes Framework for all NHS hospitals through NHS

Reference Costs. Adjustments for mortality suggest that approximately 119,000 new cases of

chronic kidney disease (CKD) were diagnosed in 2009 (Kerr 2012). A study conducted in France

estimated the annual incidence rate (IR) of CKD Stage 3 to 5, (defined as estimated glomerular

filtration rate [eGFR]<60 mL/min per 1.73m2) at 977.7 per million inhabitants (Ayav 2016). In

the United States, the adjusted IR of end-stage renal disease (ESRD) in 2015 was estimated to be

357/million/year (United States Renal Data System 2017).

A recent review of population studies of CKD conducted in Europe reported the age-adjusted

prevalence of CKD Stage 3 to 5 ranged from 1.0% (95% confidence interval [CI]: 0.7-1.3) in

Italy to 5.9% (95% CI: 5.2-6.6) in Germany for people aged 20 to 74 years. For Stages 1 to 5, the

prevalence ranged from 3.3% (3.3-3.3) in Norway to 19.4% (18.1-20.7) in Germany (Bruck

2016). In a nationally representative population-based study in Portugal, the overall prevalence

of CKD was 6.1% and the prevalence was 5.6%, 0.3%, and 0.18% for Stages 3, 4, and 5,

respectively (Vinhas 2011). Data from a representative sample of 743,935 adults in England in

2010 observed that a 21.2% of the total General Practice Research Database population, or

approximately 600,000 people, had a classification of mildly impaired eGFR, and for Stages 3 to

5 the prevalence was 5.9% (165,942). The most common stage reported was 3a at 4.0%

(Jameson 2014). In Italy, a crude prevalence rate of 7.05% (95% CI: 6.48-7.65) was calculated

based on a total sample of 8,693 people aged 35 to 79 (De Nicola 2015). A similar prevalence

(approximately 7%) was observed in a population-based study in Romania (Cepoi 2012). The

same study observed the prevalence of Stage 3a CKD to be approximately 6% and the

prevalence of Stages 3b, 4, and 5 CKD combined to be approximately 1%. According to the

2007 to 2012 National Health and Nutrition Examination Survey (NHANES) in the United

States, the prevalence of CKD in adults aged 20 and over was 13.6%. Among these, the

prevalence rate for Stage 3 CKD was approximately 6% (Saran 2015a).

End-stage Renal Disease

Anaemia develops early in the course of renal disease and progresses with loss of renal function

(Astor 2002; Kazmi 2001). Approximately 5% of patients with an eGFR between 30 and

59 mL/min/1.73 m2 body surface area (BSA) and 44% of patients with eGFR between 15 and

29 mL/min/1.73 m2 BSA are anaemic (Astor 2002). In patients who have progressed to ESRD,

anaemia is a ubiquitous comorbidity (United States Renal Data System [USRDS] 2010). In the

United States, anaemia (defined as serum HGB levels ≤12 g/dL in women and ≤13 g/dL in men),

was twice as prevalent in people with CKD (15.4%) as in the general population (7.6%). The

prevalence of anaemia increased with stage of CKD, from 8.4% at Stage 1 to 53.4% at Stage 5.


21

A total of 22.8% of CKD patients with anaemia reported being treated for anaemia within the

previous 3 months: 14.6% of patients at CKD Stages 1 to 2 and 26.4% of patients at Stages 3 to 4

(Stauffer 2014).

Children

Several paediatric nephrology societies from European countries have provided data on the early

stages of CKD, including the European Society for Paediatric Nephrology and the European

Renal Association and European Dialysis and Transplantation Association (ERA-EDTA).

Between 2009 and 2011, in 37 European countries, a total of 1,697 patients aged 0 to 14 years

started renal replacement therapy (RRT). The average overall IR of paediatric RRT was 5.5 per

million of the age-related population (pmarp). In 9 countries that collected data from paediatric

and adult centres in a registry, the IR was 8.3 pmarp for children aged 0 to 19 years and 13.3 for

children aged 15 to 19 years (Chesnave 2014). This registry reported that for patients where

complete data was available, 21.3% of patients had subtarget HGB levels, using the United

Kingdom (UK)-NICE (National Institute for Health and Care Excellence) guidelines of a target

HGB of 10.0 to 12.0 g/dL (Krischock 2016). In every registry examined in a review of the

literature, the incidence of RRT was twice as high in the United States as in Western Europe in

the 15- to 19-year-old age group (30.6 versus 15.3) and was higher in the 0- to 14-year-old age

group (10.5 versus 6.5 in Western Europe). This difference might be partly explained by the

timing of initiation of RRT (Harambat 2012).

At the end of 2011, there were 3,595 RRT patients aged 14 years and under in 37 European

countries, resulting in a point prevalence rate of 27.9 pmarp. Prevalence varies significantly

among these countries with an interquartile range of 21.8 to 43.9 pmarp. In the 9 countries that

collected data from paediatric and adult centres, the prevalence rate was 58.0 pmarp for children

aged 0 to 19 years and 109.0 for children aged 15 to 19 years (Chesnaye 2014). In 2012 in the

United States, 7,522 children (<19 years old) had prevalent ESRD, which represents a

1.3% decrease from the previous year (Saran 2015b).

In the United States, anaemia has been described as a universal problem among children with

CRF (Koshy 2008). This contrasts with McClellan’s observation that approximately half of

adults with CRF have anaemia (McClellan 2002; McClellan 2004). Among children, as among

adults, the prevalence of anaemia increases with the severity of CRF. For instance, among

patients ages 2 years and older in the North American Paediatric Renal Trials and Collaborative

Studies (NAPRTCS) database, the prevalence of anaemia increased from 18.5% in Stage 2 CRF

to 68% in Stage 5 CRF (Staples 2009).

Among paediatric patients with CRF, anaemia, (defined here as a HGB concentration <12 g/dL

or treatment with iron or darbepoetin alfa) was observed in a Canadian study in 31% of patients

with Stage 1 disease and 93% of those with Stage 4 or 5 disease (Wong 2006).

Ardissino suggests that paediatric CRF usually progresses to ESRD by age 20 (up to 68% of

patients overall) (Ardissino 2003). Therefore, it is likely that nearly all paediatric patients, other

than those with mild CRF, will at some point develop anaemia, either as they progress toward

ESRD, or at an earlier stage of the disease.


22

Demographics of the Target Population

Adults

In a review of studies on the prevalence of CKD Stages 3 to 5 in adults in Europe, the lowest rate

was in those aged 20–44 years, and increased with age (Bruck 2016). According to data from a

sub-sample of almost 10,000 adults in the United States (US) NHANES 2001-2010, those with

CRF were older (mean age, 64.2 years) than those without (Kuznik 2013). For ESRD in the

United States in 2012, the adjusted prevalence per million was 83 for ages 0 to 19 years, 938 for

ages 20 to 44 years, 3,550 for ages 45 to 64 years, 6,302 for ages 65 to 74 years, and 6,261 for

ages 75+ years (Saran 2015b).

In the United Kingdom in 2010, 92.9% of patients with Stage 3 to 5 CKD were over 60 years of

age, and only 0.5% were between the ages of 18 and 39 (Jameson 2014).

An Italian study of adults between the ages of 35 and 79 years observed a crude prevalence rate

for all CKD patients to be 2.65% (2.05-3.34) for ages 35 to 49 years, 3.41% (2.61-4.37) for ages

50 to 59 years, 8.71% (7.44-10.11) for ages 60 to 69 years, and 16.97% (15.09-18.99) for ages

70 to 79 years (De Nicola 2015).

Sex

In a large nationally representative sample from the United Kingdom, the prevalence of CKD

was higher in women than men, 47.5% of all identified CKD patients were men (Jameson 2014).

Similar findings are observed in the US NHANES 2001-2010, where 58% of those with CRF

were women (Kuznik 2013). However, men with CRF are 50% more likely than women to

progress to ESRD (CDC 2010).

In contrast, an Italian study observed a slightly higher crude prevalence rate for men

(7.54% [6.72-8.42]) compared with women (6.54% [5.76-7.38]) for all CKD patients. For

Stage 5 disease, the crude prevalence rate was 0.13% (0.04-0.30) for men and 0.11% (0.03-0.28)

for women (De Nicola 2015). A systematic review of the literature reported that male patients

showed a higher hazard ratio (HR) for progression to ESRD than women, (HR 1.37, 95% CI:

1.17–1.62), (Tsai 2016).

Race

In the most recent USRDS using NHANES data from 2007 to 2012, the prevalence of all CKD

was 13.9% for non-Hispanic Whites, 15.9% for non-Hispanic Blacks, and 11.7% for Other

(Saran 2015a). Based on statistics provided by the National Kidney Disease Education Program

(NKDEP) in the United States, compared with Whites, African Americans have 3.8 times higher

risk for kidney failure, Native Americans 2 times higher, and Asians 1.3 times higher

(NKDEP 2011).

In the Prevalence of Anaemia in Early Renal Insufficiency study (McClellan 2004), 2 thresholds

for anaemia were defined; the first at a HGB concentration of 12 g/dL and the other at a HGB

concentration of 10 g/dL. The study demonstrated that, relative to Caucasian patients, the odds


23

ratios (ORs) for having anaemia at these respective thresholds among African-American patients

with CRF were 1.6 and 2.0, respectively, and among Hispanic patients with CRF, the ORs were

1.5 and 1.6, respectively.

Children

Sex

A consistent finding in Europe is that there is a predominance of male children who have CKD

(male/female ratio ranging from 1.3 to 2.0) reflecting, in particular, the higher incidence of

congenital anomalies of the kidney and urinary tract in boys than girls (Harambat 2012). Males

account for 55% of adolescents with ESRD, and have been found to have a slightly higher IR

(24.1 per million) than females (21.0 per million) (Ferris 2006).

Race

Among adolescents with ESRD, those from minority backgrounds have the highest incidence of

ESRD. Rates by ethnicity are as follows: African American, 41.0 per million; Native American,

26.2 per million; Asian/Pacific Islanders, 24.9 per million; and Whites, 18.8 per million

(Ferris 2006). Furthermore, focal segmental glomerulosclerosis, the main cause of glomerular

disease, is especially common among Black adolescents (NAPRTCS 2008).

In the United Kingdom, in 2008, the prevalence and incidence of RRT in children from the South

Asian population were 2.5 and 1.5 times greater, respectively, than that of the White population

aged 1 to 15 years old (Harambat 2012).

Risk Factors for the Disease

Initiating factors that play a role in starting the cycle of nephron loss, include older age, male

sex, diabetes, and perpetuating factors that drive the disease process onward, include proteinuria,

hypertension, or hyperuricaemia (Tsai 2016). Other risk factors include automimmune diseases,

systemic infections, urinary tract infections, nephrolithiasis, lower urinary tract obstruction,

hyperuricaemia, acute kidney injury, and a family history of the disease. Sociodemographic

factors that increase the risk of CKD include older age, black race, smoking, heavy alcohol use

and obesity (Drawz 2015). According to data from the United Kingdom (UK) Renal Registry,

the prevalence of RRT was also higher in socially deprived areas of the United Kingdom.

Currently, diabetes mellitus is the most common cause of RRT for ESRD affecting more than

22% of the incident patients (Harambat 2012).

Main Treatment Options

Chronic kidney disease has no cure, but depending on the underlying cause, some types can be

treated. Treatment consists of measures to help control signs and symptoms of CKD, reduce

complications, and slow the progression of the disease. Kidney failure complications can be

controlled to make the patient more comfortable and include angiotensin-converting enzyme

(ACE) inhibitors or angiotensin-II receptor blockers to preserve kidney function and lower blood

pressure, statins to lower cholesterol, erythropoietin supplements to induce production of more


24

red blood cells (RBCs), in which loss is associated with anaemia, diuretics to maintain balance of

fluids in the body, and calcium and vitamin D supplements. Treatment for patients with ESRD

requires dialysis or a kidney transplant (Mayo Clinic 2015, chronic kidney failure).

Mortality and Morbidity

Adults

In a large retrospective study among patients with incident CRF in a health maintenance

organisation in the United States, patients with the most severe anaemia (HGB <10.5 g/dL) had

more than a 5-fold increased risk of mortality (HR=5.27; 95% CI: 4.37-6.35) compared with

patients who were not anaemic (Thorp 2009). Anaemia has been shown to be an independent

predictor for increased coronary heart disease mortality and all-cause mortality in patients with

CRF (Astor 2006). Among patients with ESRD, cardiovascular disease (CVD) accounts for more

than half of all deaths, and after a hospitalisation for congestive heart failure (CHF), carries a 2-

year mortality of 58% among patients with ESRD (Collins 2003). Conversely, among patients

with CHF who were admitted to community hospitals, the relative risk (RR) of mortality in the

year after hospitalisation for those with CRF compared with those without CRF was 1.4 (95%

CI: 1.2, 1.8) and RR for anaemia (relative to those without anaemia) was 1.6 (95% CI: 1.2, 2.2).

Relative risk for both CRF and anaemia together relative to those with neither was 2.2 (95% CI:

1.4, 3.3) (McClellan 2002). In a large database of patients with left ventricular dysfunction,

lower values of glomerular filtration rate (GFR) and lower HCT values were associated with

increased mortality, and the 2 together were associated with greater mortality than would be

predicted by both factors acting independently (Al-Ahmad 2001). In contrast, the results of a

clinical trial (Pfeffer 2009), described in the following paragraph, suggested that correction of

anaemia in patients with CRF, to a target HGB of 13 g/dL, did not reduce mortality (Pfeffer

2009).

In a UK prospective cohort study of people with CKD, the mortality rate was 6.5% per year

(Landray 2010). A meta-analysis has demonstrated that the risk of mortality in CRF rises

exponentially with decreasing GFR. Mortality in ESRD patients is very high. Five-year mortality

rates in incidence in patients with RRT are 52% (all patients), 32% (for those 15 to 64 years of

age), and 73% (for those over 65 years of age). Five-year mortality in patients on dialysis is

almost 5 times as high as that after kidney transplantation: 60% and 13%, respectively. Mortality

is lower in Europe compared with the United States (Zoccali 2009).

For the year 2012, in the United States the 5-year survival probability for ESRD patients

initiating treatment was 87.0% for children 19 years and younger, 73.0% for ages 20 to 44 years,

53.3% for ages 45 to 64 years, 33.0% for ages 65 to 74 years, and 15.8% for ages 75+ years

(Saran 2015b).

Children

The mortality rate in children with RRT is about 30 times higher than in their healthy peers.

Infants with severe renal disease are at higher risk of death in the first 2 years of life, but

outcomes thereafter are comparable to those of older children. The 2 major causes of mortality in


25

paediatric patients with RRT are CVD and infections, accounting for 30% to 40% and

20% to 50% of deaths, respectively. Also, the burden of morbidity from CVD and infection is

high, as, for example, infections cause 600 admissions per 1,000 person years (PY) in the first

month of starting dialysis according to the most recent USRDS report (Harambat 2012).

In Europe, for the 37 countries that report to the European Society for Paediatric Nephrology,

European Renal Association (ERA), and European Dialysis and Transplantation Association

(EDTA) registries, for children on RRT, the overall 4-year survival rate for ages <19 years was

93.7% for 2007 to 2011, while for ages 0 to 4 years it was 87.1%, for ages 5 to 9 years it was

95.3%, for ages 10 to 14 years it was 96.2%, and for ages 15 to 19 years it was 96.3% (Chesnaye

2014). In the United States from 2007 to 2011, the 1-year all-cause mortality rate (per 1,000) for

children with ESRD was 85 for ages 0 to 4 years, 39 for ages 5 to 9 years, 11 for ages 10 to 14

years, and 23 for ages 15 to 19 years. This represents an overall decrease of 22.2% compared

with 2002 to 2006 (Saran 2015b)

Cancer


A review summarised that anaemia is a frequent finding in cancer patients and occurs in more

than 40% of cases, with the incidence rising to 90% in patients treated with chemotherapy

(Dicato 2010). However, another review observed that anaemia prevalence was dependent on the

definition of anaemia; for example, 7% of patients with Hodgkin’s disease had anaemia when the

condition was defined as a HGB level <90.0 g/L while as many as 86% of patients had anaemia

when it was defined as a HGB value <110 g/L. Prevalence also varied by cancer type and disease

state; 40% of patients with early-stage colon tumours and nearly 80% of patients with advanced

disease had anaemia (Knight 2004).

The European Cancer Anaemia Survey (ECAS) (Ludwig 2004) was conducted to document the

prevalence, incidence, evolution, severity, and management of anaemia in a large, representative

population of European patients with cancer. It was a prospective, epidemiologic, observational

survey conducted in 748 centres in 24 European countries. It defined anaemia as

HGB <12.0 g/dL, with the following subclassifications based on HGB concentration:

HGB 10.0 to 11.9 g/dL (mild), 8.0 to 9.9 g/dL (moderate), and <8.0 g/dL (severe). The ECAS

also indicated that the severity of anaemia increased with the number of cycles of chemotherapy

and varied according to cancer type and therapy. Reports from the ECAS estimate the incidence

of anaemia to be 59.8% for patients with breast cancer and 74.8% for patients with gynaecologic

cancer, while 62.4% of patients with breast cancer and 81.4% of patients with gynaecologic

cancer were anaemic at some time during the survey. Similarly, 83.3% of patients with lung

cancer who received chemotherapy were anaemic at some time during the survey

(Barrett-Lee 2005; Kosmidis 2005). Another analysis of ECAS data reported that for lymphoma

and multiple myeloma patients anaemia prevalence was 72.9%, and incidence in chemotherapy

patients was 55.4% (Birgegård 2006). In patients not receiving antineoplastic treatment, anaemia

was present in 32%, including 25% of patients considered to be in remission (Gascon 2006). A

Finnish study of patients who received chemotherapy for solid tumours, 27% had a HGB level


26

<12 g/dL, (Kellokumpu-Lehtinen 2011). In Germany, a study conducted in patients treated on an

outpatient basis for any tumour type reported that 49.1% of the patients had HGB concentrations

below 12.0 g/dL and 10.9% had concentrations below 10.0 g/dL (Link 2013). All of these studies

demonstrate that anaemia affects a large proportion of cancer patients regardless of the type of

tumour.


Age

Anaemia occurs most often in older individuals, with its prevalence in elderly patients with

cancer significantly increasing (Penninx 2007). A Spanish study reported the median age of

cancer patients with anaemia was 63 years (Steegmann 2013). Based on data from the ECAS,

44% of elderly patients (>69 years) were anaemic at time of enrolment, compared with 40% of

patients 60 to 69 years of age, and 36% of patients 50 to 59 years of age (Birgegård 2005).

Similarly, a German study, using the same definition of anaemia (HGB levels below 12 g/dL),

reported anaemia prevalence of 45.6% for those ≤65 years, and 52.8% for those >65 (Link

2013).

Sex

In the ECAS, female gender was observed to be an independent predictor of anaemia

(Barrett-Lee 2006).


Risk factors for anaemia in patients with cancer could include nutritional deficiencies, major

organ problems, lower initial HGB (≤12.9 g/dL in women and ≤13.4 g/dL in men), having lung

or gynaecologic cancer versus gastrointestinal or colorectal cancer, treatment with platinum

chemotherapy, and female gender (Barrett-Lee 2006; American Cancer Society 2014).

Specifically, in patients with breast cancer, risk factors for anaemia could also include exposure

to taxanes, high-dose anthracycline treatment, mastectomy, and being over 60 years of age

(Chaumard 2012).


Treatment options for treating anaemia in patients with cancer can include eating nutrient-rich

foods, taking iron and folic acid supplements, blood transfusions, and drugs such as

erythropoietin that help the body make its own new RBCs (American Cancer Society 2014).


Anaemia may adversely affect survival in patients with cancer. In a comprehensive literature

review of survival with and without anaemia, an association of anaemia with reduced survival

times was observed consistently for carcinoma of the lung, cervix, head and neck, prostate,

lymphoma, and multiple myeloma (Caro 2001). Similarly, survival probability for cancer

patients with anaemia severity Grade 2 (HGB <10.0 g/dL) was significantly lower than for

patients with no anaemia (Nakamura 2011). A recent systematic review of studies on outcomes

of blood transfusions for anaemia in patients with advanced cancer observed a significant


27

proportion of participants (23% to 35%) dying within 2 weeks of their transfusion. Overall

survival for inpatients receiving transfusion was lower (35 days versus 86 days) than that for

outpatients (Preston 2012).



The incidence of autologous blood donation (ABD) is not detailed in the literature.

The most recent data found on the prevalence of ABD comes from a questionnaire in 2000 from

43 member states of the Council of Europe. The responses indicated that predeposit ABD is not

practised anywhere on a very large scale but it is moderately common (4.6% to 7.8% of allogenic

blood) in Italy, Germany, France, Czech Republic, and Luxembourg. Up to 533,839 predeposit

units were collected in Europe in 2000, which is equivalent to 3.3% of the allogeneic units

donated in the same year. The autologous units issued in 2000 represented 85% of those

collected, and those used represented 70% of those collected, although there were wide

variations between countries (Politis 2004). In the United States, ABD represented 4.0% of all

blood donations (Goodnough 2004). In the United States for the years 2008-2011, of the more

than 3,500,000 patients who underwent elective orthopaedic surgery, 2.4% received an

autologous blood transfusion (Menendez 2014).

In Spain, preoperative ABD has increased from 15,123 units in 1994 to 24,390 units in 2004

with fluctuations between years. The most common area of application of preoperative ABD was

orthopaedic surgery procedures, where 80% of the collected preoperative ABD units were

actually transfused (Garcia-Erce 2007). A study conducted in the United States showed that 16%

of total hip arthroplasties were performed in anaemic patients (HGB <12.5 g/dL), and 76% of

them had an ABD prior to surgery (Bou Monsef 2014).


Few studies have discussed the demographics of ABD. One study (Martin 2010), examined all

patients who donated autologous blood prior to cardiac surgery who were matched to a

non-donor according to age, body weight, body mass index (BMI), sex, and other covariates. The

average age of the donors was 58 years old and there were more men than women

(156 versus 60, respectively). The average BMI was 26, which is considered overweight. In the

United States, black and Hispanic patients receiving elective orthopaedic surgery were less likely

to receive an autologous blood transfusion than white patients (Menendez 2014).


Risk factors for ABD include becoming anaemic, hypovolaemic, or having a low blood count

before surgery.


Not applicable.


28


Autologous blood donation is a preoperative procedure and therefore literature on morbidity and

mortality is scarce. The aforementioned study (Martin 2010) observed that there were no major

adverse events such as myocardial infarction (MI), stroke, or death in the donor group during the

preoperative ABD process. Approximately 1 in 16,783 autologous donations is associated with

an adverse reaction severe enough to require hospitalisation, which is 12 times the risk

associated with community donation by healthy individuals (Goodnough 2004).

Surgery


Hip replacement

The rates of hip and knee replacement surgeries have increased in several European countries in

the past 10 years, mostly due to the ageing population. In a study of data from 2014, Germany,

Austria, Belgium, and Finland had the highest rates of hip replacement (293, 279, 247, and

245 surgeries per 100,000 population, respectively) among European countries, and Switzerland

had a rate of 305/100,000 population. The overall rate of hip replacement for the EU27

(Germany, Austria, Sweden, Finland, Belgium, France, Denmark, Luxembourg, Netherlands,

Slovenia, United Kingdom, Greece, Czech Republic, Italy, Hungary, Croatia, Lithuania, Ireland,

Latvia, Spain, Slovak Republic, Estonia, Portugal, Poland, Malta, Romania, Cyprus) was 189 per

100,000 population (OECD/EU 2016).

Knee replacement

In the same study from 2014, Austria, Germany, Belgium, and Finland had the highest rates of

knee replacement (221, 197, 191, and 190) per 100,000 population, respectively, Switzerland had

a rate of 214/100,000 population. The overall rate of knee replacement for the EU25

(Austria, Finland, Germany, Belgium, Luxembourg, Denmark, Malta, Sweden, United Kingdom,

France, Netherlands, Czech Republic, Slovenia, Spain, Italy, Lithuania, Portugal, Hungary,

Cyprus, Croatia, Ireland, Latvia, Poland, Romania, Slovak Republic) was 130 per 100,000

population (OECD/EU 2016).

A systematic review of 19 studies on anaemia prevalence in patients undergoing major

orthopaedic surgery reported preoperative anaemia to be highly prevalent, ranging from

24% among patients undergoing total hip replacement (THR) or total knee replacement (TKR)

surgery to 44% among patients undergoing hip fracture surgery. Prevalence of postoperative

anaemia was 51% in patients undergoing hip or knee replacement surgery (Spahn 2010) and

20.5% of THR patients had an HGB level <10g/dL on the day of discharge (Jans 2016). As

mentioned above, a US study of total hip arthroplasty patients, 16% were performed in anaemic

patients (HGB <12.5 g/dL) (Bou Monsef 2014). A Danish study of THR and TKR procedures

reported that 12.8% of patients had preoperative anaemia (Jans 2014) and an Austrian study

reported preoperative anaemia rates of 17% and 16% for THR and TKR respectively (Gombotz

2014).


29


Hip and knee replacement surgery is mainly carried out among people aged 60 and over, for

severe osteoarthritis, but it can also be performed on younger patients (OECD/EU 2016). In the

United Kingdom, 1 study reported that 62.2% of THR patients were women with a mean age of

69.9 years and 37.8% were men with a mean age of 67.8 years. For TKR patients, 58.4% were

women with a mean age of 70.3 years while 41.6% were men with a mean age of 69.4 years

(Culliford 2015)

A systematic review of the epidemiology of hip and knee arthroplasty reported higher rates in

Caucasians than in African Americans. Similar arthroplasty utilisation rates were observed in

men and women in 3 studies based in the United States, Denmark, and England (Singh 2011).


The leading diagnoses for patients in the United States who underwent THR in 2003 were

osteoarthritis (OA, 81%), other bone/musculoskeletal disease (9%), and fracture of the femoral

neck (4%). For partial hip replacement (PHR), the most frequent diagnoses were fracture of the

femoral neck (88%), pathologic fracture (3%), and other bone/musculoskeletal disease (3%). For

PHR, the most frequent principal diagnoses were complication of the device, implant, or graft

(89%); OA (2%); and fracture of the neck of the femur (2%). Approximately 60% of the patients

treated with THR or PHR were 65 years of age or older, and most of their admissions to the

hospital were planned. About 80% of the patients treated with PHR were age 75 years or older

and about 80% of their admissions were emergency admissions. Thus, the epidemiology of

surgery for THR together with PHR provides a reasonable approximation to the epidemiology of

elective hip replacement surgery (Zhan 2008; Löfvendahl 2011). The main indication for TKR is

arthritic deterioration of the joint (NIH Consensus Panel 2004; Mayo Clinic 2013, knee

replacement). Therefore, most TKRs are elective.


Not applicable.


A systematic review of 32 studies published over the last decade that provided mortality data

post-THR surgery estimated the pooled mortality rate to be 0.30% (95% CI: 0.22-0.38) at

30 days and 0.65% (95% CI 0.50-0.81) at 90 days following hip replacement (Berstock 2014).

A Danish study examining THR and TKR procedures reported that 12.8% of the patients had

postoperative anaemia. The mortality rate of 1.1% for those with preoperative anaemia was

significantly higher than the mortality rate for those who did not have anaemia (0.3%), and the

mortality rate for all THR and TKR patients was 0.4% (Jans 2014). A systematic review of

studies on the epidemiology of anaemia in patients undergoing major orthopaedic surgery

observed both preoperative and postoperative anaemia to be associated with increased mortality

in all 3 prospective studies that investigated this association. Overall ORs for death were

increased 1.5- to over 2-fold in anaemic versus non-anaemic patients (Spahn 2010).


30

Myelodysplastic Syndromes


Orphanet estimates the incidence of MDS to be 1.5/100,000 in Europe (Orphanet 2017).

Similarly, the annual IR of MDS is 3.8 per 100,000 in the United Kingdom with an age

standardised rate (ASR) of 2.6/100,000 according to the Haematological Malignancy Research

Network (HMRN 2017), which is a collaboration between research at the University of York, a

clinical network of 14 hospitals, and St. James’ hospital in Leeds. In the Netherlands, the ASR

was estimated to be 2.8/100,000 in 2006-2010 (Dinmohamed 2014). Prevalence data for MDS in

the EU are available from few sources. Prevalence of MDS was estimated based on data from

22 European cancer registries through the RARECARE (Surveillance of Rare Cancers in

Europe) project. The estimated complete prevalence as of 01 January 2008 was 24,958 persons

in the EU, corresponding to a prevalence of 0.50 per 10,000 persons (Visser 2012). A prevalence

of 0.50 per 10,000 population for MDS was also consistently reported from a systematic review

of the literature on rare diseases in Europe (Orphanet, 2015). Recent data (2005-2014) from the

HMRN in the United Kingdom estimate the 3-, 5-, and 10-year prevalence of MDS as 7.7, 9.9,

and 12.2 per 100,000 persons, respectively (HMRN 2017). In addition, population-based data on

MDS from the Dusseldorf MDS Registry in Germany during 1996 to 2005 indicated that the

crude point prevalence of MDS according to the World Health Organisation classification was

1.14 per 10,000 persons (age-standardised prevalence: 0.72 per 10,000 in 2003, while the point

prevalence of MDS according to the French-American-British classification was 1.28 per 10,000

persons (age-standardised prevalence: 0.81 per 10,000 persons) (Neukirchen 2011).

Demographics and the Target Population

Age

Myelodysplastic syndrome is a disease of the elderly, with a median age at diagnosis of over

70 years and with less than 10% of patients being younger than 50 years of age (Fenaux 2014;

Neukirchen 2011). Similarly, the United Kingdom data demonstrated that the median age at

diagnosis is 75.7 years (HMRN 2015).

Race

A review noted that although there are no known ethnic differences in the incidence of MDS, the

disease tends to occur at an earlier age in Asian populations (Fenaux 2014). However, another

review from the United States noted that MDS was most prevalent in Whites (Ma 2012)

Geography

Data from the HAEMCARE project (Sant 2010) that included data from 48 European cancer

registries observed that for MDS, 66% of cases were in Ireland and the United Kingdom and

16% in Northern Europe; Central, Southern and Eastern Europe reported 7%, 9%, and 2%,

respectively (Maynadié 2013).


31


A review noted that the aetiology of MDS is known in only 15% of cases (Fenaux 2014). An

inherited predisposition to MDS should be assessed in patients with Down’s syndrome, Fanconi

anaemia, and neurofibromatosis, as well as MDS occurring in young adults or in families with

other cases of MDS, acute myeloid leukaemia, or aplastic anaemia. Environmental factors could

include previous use of chemotherapy, especially alkylating agents and purine analogues

radiotherapy or ionizing radiation, and tobacco smoking. Recognized occupational factors

include benzene and its derivatives, while excess MDS cases have also been observed in

agricultural and industrial workers.


The assessment of individual risk enables the identification of fit MDS patients with a poor

prognosis who are candidates for upfront intensive treatments, primary allogenic stem cell

transplantation. A high proportion of MDS patients are not eligible for potentially curative

treatment due to advance age and/or clinically relevant comorbidities and poor performance

status. In these patients, the therapeutic intervention is aimed at preventing cytopenia-related

morbidity and preserving quality of life. In high-risk MDS patients, treatment using

hypomethylating agents such as azacitidine is recommended. When azacitidine or decitabine

administration is not possible, low-dose cytarabine is a treatment option for higher-risk MDS

patients. For lower-risk MDS patients, the main priority is treatment of cytopenias, mainly

anaemia. Chronic RBC transfusions, ESAs (ie, recombinant endogenous erythropoietin or

darbepoetin, lenalidomide) are treatment options for low-risk MDS. Second-line treatments for

low-risk MDS include anti-thymocyte globulin, hypomethylating agents, and lenalidomide. Iron

chelation therapy is also used for low-risk MDS with favorable prognosis (Fenaux 2014).


Patients with MDS have poor survival, with the 5-year relative survival being only 28.2%

(HMRN, 2015). Specifically, according to the revised International Prognostic Scoring System

(IPSS) for MDS, the median overall survival for patients in the different risk groups is as

follows: 8.8 years for very low risk, 5.3 years for low risk, 3 years for intermediate risk, 1.6 years

for high risk, and 0.8 years for very high-risk patients (Fenaux 2014).


32

SI.2. Concomitant Medication(s) in the Target Population

Chronic Renal Failure – Adult Patients

Comorbidity Medications

Cardiovascular disease Statins, fibrates, ACE inhibitors or beta blockers, angiotensin-IIreceptor antagonists, diuretics, anticoagulants, and antiplatelet medications

Hypertension Classes of blood pressure medications include diuretics, beta blockers, ACE inhibitors, angiotensin-II receptor blockers, calcium channel blockers, alpha blockers, alpha-2 receptor agonist, and combined alpha and beta blockers

Diabetes mellitus Insulin and oral hypoglycaemic agents

Hepatitis Antiviral medications

Cancer Chemotherapy, radiotherapy, hormonal therapy, drugs used for targeted therapy, and immunotherapy

Thrombosis Anticoagulants, thrombolytic agents, antiplatelet medications

ACE=angiotensin-converting enzyme

Chronic Renal Failure – Paediatric Patients



Hepatitis Antiviral medications

Short stature Growth hormone treatment

Thrombosis Anticoagulants, thrombolytic agents, antiplatelet medications



33

Cancer



Diabetes Insulin and other hypoglycaemic agents


Renal failure High blood pressure medications, medications to lower cholesterol levels, medications to relieve anaemia, anti-inflammatory medications, and medications to protect bones

Cerebrovascular disease Aspirin, heparin, clopidogrel, warfarin, dipyridamole, tissue plasminogen activator

Myelosuppression/infection Antibacterials for febrile neutropenia, colony-stimulating factors for neutropenia, possible blood transfusion for anaemia, or prophylactic administration of platelet concentrate



Autologous blood donation is a procedure and not a condition; therefore, there are no associated

comorbidities.


34

Surgery


Obesity Prescription weight loss medication in certain situations

Osteoarthritis Acetaminophen, nonsteroidal anti-inflammatory drugs, narcotics. Non-conservative treatments include cortisone injections and lubrication injections

Cardiovascular

disease

Statins, fibrates, ACE inhibitors or beta blockers, angiotensin-IIreceptor antagonists, diuretics, anticoagulants, and antiplatelet medications



Myelodysplastic Syndrome



Diabetes Insulin and oral hypoglycaemic agents

Cerebrovascular diseases Antihypertensives, cholesterol-lowering medications, antiplatelet medications, thrombolytics, anticoagulants, tissue plasminogen activator

Prior malignancies Chemotherapy, radiotherapy, hormonal therapy, drugs used for targeted therapy, and immunotherapy



35

SI.3. Important Comorbidities Found in the Target Population

Chronic Renal Failure – Adult Patients

Comorbidity: Cardiovascular Disease

Incidence of CVD:

Cardiovascular disease is frequently associated with CKD. In a population-based study in

Germany, the IR of MI among persons with CKD was 146.5 per 10,000 PY in men and 48.2 per

10,000 PY in women (Meisinger 2006). A retrospective cohort study that used the US Medicare

database observed a 13% increased rate of incident atrial fibrillation in patients with Stages 3 to

5 CRF (HR=1.13; 95% CI: 1.09-1.18) compared with patients without CRF (Nelson 2012).

Prevalence of CVD:

In a large, nationally representative sample of adults in England, heart failure was prevalent in

52.5%, ischaemic heart disease in 33.4%, and peripheral vascular disease in 36.3% of patients

with CKD (Kearns 2013). In another UK study involving primary care computerised records, the

prevalence of ischaemic heart disease was 25% for patients with CKD Stages 3 to 5

(de Lusignan 2005). Another UK study using the General Practice Research Database observed

that 37.1% of patients with Stage 3 to 5 CKD also had CVD as did 27.7% of patients with Stage

5 CKD (Jameson 2014).

Mortality of CVD:

In a population-based German study, the CVD mortality rate among patients with CKD was

189.8 per 10,000 PY in men and 87.1 per 10,000 PY in women (Meisinger 2006). A review of

the literature (Johnson 2007) concluded that CVD accounted for 40% to 50% of deaths in

patients undergoing dialysis, and these populations have a 10- to 20-fold increased risk of

cardiovascular mortality relative to age and sex-matched comparators without CKD. Similarly,

in a retrospective cohort study that used US Medicare data, the 1-year mortality rate for

Stages 3 to 5 CRF with incident atrial fibrillation was 35.6% (Nelson 2012).

Comorbidity: Hypertension

Incidence of hypertension:

Hypertension is very common among patients on haemodialysis or peritoneal dialysis, and those

who have undergone renal transplant (Tedla 2011). Arterial hypertension develops in up to 80%

of renal transplant recipients (Basić-Jukić 2007). The term “hypertension” in the discussion of

incidence and prevalence is used as the inclusive term, and so may include occurrences of

hypertensive crisis or other related terms.

Prevalence of hypertension:

In a large nationally representative sample of adults in England, hypertension was prevalent in

41.5% of patients with mildly impaired eGFR, 63.9% of those in Stage 3 to 5 CKD, and 79.3%

of those in Stage 5 CKD (Jameson 2014). Hypertension prevalence was reported in 3.0% of all

CKD patients in a US national survey of non-institutionalised adults (Saran 2015a), which


36

estimates that hypertension occurs in 35.8% of Stage 1, 48.1% of Stage 2, 59.9% of Stage 3, and

84.1% of Stage 4 to 5 patients with CRF (USRDS 2010). Similarly, in a Canadian population-

based survey, the prevalence of hypertension in adults with CRF was 24.4% compared with 15%

in patients without CRF. Furthermore, hypertension prevalence was more than double among

those with Stage 3 to 5 CKD than with Stage 1 or 2 CKD (52.8% versus 23%, respectively)

(Arora 2013). Among complications associated with hypertension in patients with CKD, heart

failure may be exacerbated by anaemia (Silverberg 2006; Iaina 2005).

Mortality of hypertension:

In a meta-analysis of studies that included 25 general populations, 7 high-risk and 13 CKD

cohorts, CKD emerged to be an equally relevant risk factor for mortality and ESRD in

individuals without hypertension as in those with hypertension (Mahmoodi 2012b). Consistent

with these findings, in a more recent large study of US veterans with CKD, all-cause mortality

was increased both for patients in the lower (systolic blood pressure [SBP] <120 mm Hg and

diastolic blood pressure [DBP] <80 mm Hg) and higher (SBP ≥160 mm Hg or

DBP ≥100 mm Hg) blood pressure categories (Kovesdy 2013).

Comorbidity: Diabetes Mellitus

Incidence of diabetes mellitus:

In a Taiwanese national study of incident dialysis patients, the cumulative IR of

new-onset diabetes was 4% at 1 year and 21% at 9 years (Tien 2013). In an older study based on

a dialysis registry in Italy, the incidence of new diabetic patients admitted for dialysis per million

population per year was 10.3 in women and 12.9 in men (Piccoli 1992).

Prevalence of diabetes mellitus:

Diabetes mellitus is a common comorbidity and cause of CRF and ESRD. In a large nationally

representative sample of adults in England, diabetes mellitus was prevalent in 13.2% of patients

with mildly impaired eGFR, and 19.2% of those with Stage 3 to 5 CKD (Jameson 2014). In the

US adult population from 2007 to 2012, 39.2% of all CKD patients also had diabetes

(Saran 2015a). Estimates were lower in a Canadian population-based survey, where the

prevalence of diabetes mellitus in adults with CKD was 10.9% compared with 5.4% in patients

without CKD. However, diabetes prevalence was more than double among those with Stage 3 to

5 CKD than with Stage 1 or 2 disease (23.4% versus 10.8%, respectively) (Arora 2013).

Mortality of diabetes mellitus:

According to US data linking NHANES and the national death index, standardised mortality

among individuals with both diabetes and kidney disease was 31.1% (95% CI: 24.7%-37.5%)

compared with 7.7% (95% CI: 7%-8.3%) among those without the 2 diseases (Afkarian 2013).

In a Taiwanese study of incident dialysis patients, new-onset diabetes was associated with a

10% (95% CI: 3%-17%) increased mortality risk (Tien 2013).


37

Comorbidity: Hepatitis

Incidence of hepatitis:

The incidence of hepatitis C infection among 320 predialysis patients with CKD in Italy was

estimated to be 6.25%, while the incidence in the general population in Europe ranged from

0.2% to 3.5% (Cavoli 2011). In a French study of 4,718 patients undergoing chronic

haemodialysis, the estimated incidence of new hepatitis C infections per year was 0.05%

(Saune 2011). In a US study of veterans with eGFR >60 mL/min•1.73 m2 at baseline, patients

who were hepatitis C virus (HCV) positive had an IR of 16.7 (16.4-17.0)/1,000 PY for

developing an eGFR <60 mL/min•1.73 m2 compared with 14.9 (14.8-15.0)/1,000 PY in the

HCV-negative group. The adjusted HR for HCV was 1.15 (95% CI 1.12-1.17) (Molnar 2015).

Prevalence of hepatitis:

A recent update on hepatitis C prevalence in dialysis patients reported that the prevalence of

hepatitis C among dialysis patients varies worldwide, ranging from a low of 1% to a high of over

70%. Notably, the prevalence of anti-hepatitis C positive patients on long-term dialysis in

northern Europe is below 5% and around 10% in most of southern Europe (Fabrizi 2013). In a

French study of 4,718 patients undergoing chronic haemodialysis, the prevalence of

anti-hepatitis C antibodies (Abs) was 7.7% (Saune 2011).

Mortality of hepatitis:

A novel meta-analysis including 14 observational studies (n=145,608 unique patients on

long-term dialysis) demonstrated that anti-HCV-positive serological status was an independent

and significant risk factor for death in patients on maintenance dialysis (Fabrizi 2012). The

summary estimate for adjusted RR (all-cause mortality) was 1.35 with a 95% CI of 1.25 to 1.47.

The negative impact of HCV on all-cause survival in the dialysis population is consistent with

other sources. The Dialysis Outcomes and Practice Patterns Study, a prospective observational

study of representative samples of haemodialysis patients in France, Germany, Italy, Japan,

Spain, the United Kingdom, and the United States (16,720 patients followed up to 5 years)

reported an independent and significant association between anti-HCV-positive serologic status

and mortality (RR, 1.17; p<0.0159) (Goodkin 2003).

Comorbidity: Cancer

Incidence of cancer:

According to a review on CKD and cancer, kidney transplant recipients have a 3- to 4-fold

increase in overall cancer risk compared with the general population, and RRs higher than 3 for

about 20 specific tumours. After dialysis, cancer risk increases 10% to 80% according to studies

for about 10 cancer sites (Stengel 2010).

Among 24,552 participants of a large population-based study in Sweden (Christensson 2013)

that included older men (aged 60), younger men (aged 40 to 52), older women (aged 47 to 57),

and younger women (aged 35 to 43), only 3.5% of patients had moderately impaired renal

dysfunction at baseline. The proportion was higher in older patients (10% of men, 2% of women)

than younger patients (7% of men, 1% of women). For participants with


38

GFR ≥60 mL/min/1.73 m2 versus GFR <60 mL/min/1.73 m2 at baseline, the 15-year probability

of cancer was 23% versus 19% (older men), 7% versus 6% (younger men), 14% versus 13%

(older women), and 10% versus 10% (younger women). No association was observed between

moderately impaired renal function and overall long-term cancer risk except for an increased risk

of kidney cancer (HR=3.38; 95% CI: 1.48-7.71) and moderately decreased GFR in younger men.

Similarly, in a population-based case-control study conducted among the US elderly by linking

the Medicare and National Cancer Institute Surveillance, Epidemiology, and End Results

(SEER) programme data, ESRD was not associated with overall cancer risk, although risk was

increased for specific tumours (Shebl 2012). Another US study of ESRD patients 18 years or

older who received haemodialysis with no cancer diagnosis for the first 9 months of dialysis

observed that the 5-year crude cumulative incidence of any cancer accounting for death as

competing risk was 9.48% (95% CI 9.39%-9.57%) and a standardised incidence ratio of

1.42 (95% CI 1.41-1.43). This same study also observed that the cumulative incidence was

higher for the following groups: person 65 years or older at dialysis therapy initiation (11.28%),

men (10.93%), non-Whites (9.79%), non-Hispanics (9.65%), primary ESRD cause other than

diabetes (hypertension, 10.39%). The risk was highest for cancers of the kidney/renal pelvis

(standardised incidence ratio 4.03; 95% CI 3.88-4.19). In addition, having a HCV-positive status

was associated with a greater risk of developing ESRD with an adjusted HR of

1.98 (95% CI 1.81-2.16). (Butler 2015)

In a large Australian prospective population-based cohort study (Wong 2009) of 3,654 residents

aged 49 to 97 years, 711 (19.5%) cancers occurred during a mean follow-up period of 10 years.

The cumulative incidence of cancer in men with CKD was 23.1 per 1,000 PY compared with

16.8 per 1,000 PY among those without CKD. After a mean follow-up period of 10 years, 23.3%

of those with an eGFR <60 mL/min/1.73 m2 had incident cancers compared with 16.9% of those

with an eGFR >60 mL/min/1.73 m2. In contrast, among women, cumulative incidence of cancers

for those with CKD was 11.9 per 1,000 PY compared with 13.8 per 1,000 PY among those

without CKD. A total of 12% of those with an eGFR <60 mL/min/1.73 m2 developed cancers

compared with 14% of those with an eGFR >60 mL/min/1.73 m2.

Prevalence of cancer:

Among 79 patients with autosomal-dominant polycystic kidney disease (ADPKD) and CRF in a

French hospital, 50 patients had ESRD and were on haemodialysis for more than 1 year or had

received a transplant. Of 89 kidneys, 11 kidneys had carcinomas (Hajj 2009). A US study that

used US Renal Data System ESRD incident data from 1998 to 2002 reported cancer prevalence

of 31% in 236,009 ESRD patients at initiation of RRT (Xue 2005).

Mortality of cancer:

In a French prospective study of 155 elderly patients (≥80 years of age) with an eGFR below

45 mL/min/1.73 m2, after a mean duration of 24.7 months follow up, 9% of deaths were due to

cancer (Faller 2013). In another retrospective multicentre French study, of the 178 dialysis

patients who developed cancer from 1997 to 2010 after initiation of chronic dialysis, 58% died

during the 2-year follow-up period after cancer diagnosis (Janus 2013).


39

In a very recent prospective population-based cohort study from Australia, among

4,077 participants aged 49 to 97 years, the cumulative incidence of cancer deaths for those with

an eGFR <60 mL/min/1.73 m2 was 107 events/1,000 PY, compared with 95 events/1,000 PY for

those with eGFR ≥60 mL/min/1.73 m2 (Iff 2014).

Comorbidity: Thrombosis

Incidence of thrombosis:

Thrombosis, especially thrombosis of the arteriovenous fistula used for vascular access, is

common in patients with ESRD. In a large longitudinal population-based study of middle-aged

and elderly adults in the United States, the IR per 1,000 PY of venous thromboembolism (VTE)

was 1.5 in patients with normal kidney function, 1.9 in those with mildly decreased renal

function, and 4.5 in those with Stage 3 or 4 CRF (Wattanakit 2008). In a Netherlands study of

298 patients with nephrotic syndrome, the annual incidences of VTE and arterial

thromboembolism were 1.02% and 1.48% respectively. Over the first 6 months of follow up,

these rates were 9.85% and 5.52%, respectively (Mahmoodi 2008). Consistent findings were

observed in another Netherlands study of 455 patients on dialysis in whom the IR of venous

thrombosis was 5.6 times higher (95% CI: 3.1-8.9) than the rate in the general population

(Ocak 2011).

Prevalence of thrombosis:

In a US study of 268 patients, those with CRF suffered more upper extremity deep vein

thrombosis (DVT) than those without CRF (30% versus 10.8%, respectively)

(Daneschvar 2008).

Mortality of thrombosis:

In a Netherlands study of 455 dialysis patients, the all-cause mortality risk was 1.9-fold

(95% CI: 1.1-3.3) increased for patients with a history of venous thrombosis (Ocak 2011).

Chronic Renal Failure – Paediatric Patients



In a US prospective study of 140 children from 67 families with ADPKD, the incidence of

hypertension in children with ADPKD was 18% (Fick 1994).


Hypertension is found in more than 50% of paediatric patients with CKD, although its

prevalence varies according to the cause of CKD (Van DeVoorde 2011). For instance, in the

Chronic Kidney Disease in Children cohort study, 37% of children with CKD had either elevated

SBP or DBP (Flynn 2008), while the prevalence of hypertension was 79% in another

US cross-sectional study of all (n=624) paediatric long-term haemodialysis patients

(Chavers 2009).


40


Mortality data associated with hypertension in the CKD paediatric population are not available.

Comorbidity: Hepatitis

Incidence of hepatitis:

Incidence data on hepatitis in children with CKD are not available.

Prevalence of hepatitis:

Hepatitis, especially hepatitis C, has been common among paediatric patients with ESRD

receiving dialysis, sometimes affecting as many as 50% of patients on dialysis and 10% of those

with CRF not requiring dialysis (Inglot 2000). Among 100 children with CRF (34 children on

regular haemodialysis and 66 children on predialysis) in Egypt, 51% had exposure to hepatitis G

virus, 5% tested positive for hepatitis B surface antigen, 5% tested positive for hepatitis B core

antibody (Ab), and 52% had positive hepatitis C Ab (Hammad 2009).

Mortality of hepatitis in children:

The mortality rates associated with hepatitis infection in children with CKD are not available.

Comorbidity: Short Stature

Incidence of short stature:

Short stature is defined as a height below the 2 standard deviation score (SDS) for age and sex,

which approximately corresponds to the 2.5 percentile; however, this statistical definition ideally

should be used with an ethnically appropriate growth chart (Salas 2013; Oostdijk 2009). A study

based on the European study group for nutritional treatment of CRF in childhood included

321 prepubertal patients treated for CRF due to congenital renal disorders. In this study, children

with CRF had normal heights at birth but dropped below the third normal percentile during the

first 15 months of life. The difference in growth rates resulted in a mean height SDS

of -1.65±1.5 SDS and -2.79±1.4 SDS in groups with better and worse GFR, respectively

(Schaefer 1996).

Prevalence of short stature:

Linear growth is frequently decreased in children with advanced CKD, but tends to improve with

administration of recombinant human growth hormone (Kari 2005; de Graaff 2003;

Mahesh 2008). The 2006 NAPRTCS Annual Report noted that children enroled in the registry

had mean height deficits of -1.61 and -1.78 at dialysis initiation and transplantation, respectively

(Seikaly 2006).

Mortality of short stature:

In a study of children receiving dialysis, each 1.0 SDS decrease in height was associated with a

14% increase in the risk of mortality (Wong 2000). Similarly, among patients receiving dialysis

or with kidney transplants, those with moderate or severe growth failure had an increased risk of


41

hospitalisation and death (Furth 2002a). Finally, a height below the first percentile at dialysis

initiation was associated with an increased risk of hospitalisation and death (Furth 2002b).

Cancer



Several studies report on the incidence of hypertension associated with various drug therapies in

patients with cancer, with limited data on the overall incidence of hypertension in the general

cancer population. For example, a retrospective cohort study was conducted to estimate the IRs

of new-onset hypertension in adult cancer patients identified from the Varian Medical Oncology

outpatient database in the United States. New-onset hypertension was observed in about

one-third of 25,090 patients with various cancer types. The IRs of severe and crisis-level

hypertension, respectively, were the highest in patients with gastric (18.5 cases per 100 PY and

5.6 per 100 PY, respectively) and ovarian cancer (20.2 per 100 PY and 4.8 per 100 PY,

respectively). The highest IR of moderate hypertension was observed in patients with renal

cancer (46.7 per 100 PY). Across all cancers, chemotherapy exposure was associated with a 2- to

3.5-fold increase in risk of any degree of hypertension compared with periods of no

chemotherapy; higher hypertension levels demonstrated greater variability in RRs by type and

line of therapy but indicated an overall increase associated with chemotherapy exposure

(Fraeman 2013).


Among cancer patients, hypertension has been observed to be the most common comorbidity

with a prevalence of 37% (Piccirillo 2004). However, a prevalence of 29% prior to

chemotherapy has been found to be similar to the general population (Maitland 2010).


Findings from a meta-analysis (Grossman 2002) of 10 longitudinal studies that evaluated the

association between hypertension and cancer mortality in 47,119 patients observed that

individuals with hypertension experienced an increased rate of cancer mortality during durations

of follow up ranging from 9 to 20 years, with and age- and smoking-adjusted pooled odds ratio

(OR) of 1.23 (95% CI 1.11 to 1.36). In 13 case-controlled studies, including 6,964 cases of renal

cell cancer and 9.181 controls, the adjusted OR for renal cell cancer among hypertensive

patients, relative to normotensive counterparts was 1.75 (95% CI 1.61 to 1.90). Based on 7

cohorts from Norway, Austria, and Sweden, a positive association was observed for cancer

mortality for every 10-mmHg increment in men (HR=1.12; 95% CI: 1.08-1.15) and women

(HR=1.06; 95% CI: 1.02-1.11), indicating a higher risk of death associated with elevated blood

pressure (Stocks 2012).


42

Comorbidity: Diabetes

Incidence of diabetes:

The risk of new-onset diabetes among postmenopausal breast cancer survivors in a

Canadian-based study began to increase 2 years after diagnosis (HR=1.07; 95% CI: 1.02-1.12)

and rose even higher after 10 years (HR=1.21; 95% CI: 1.09-1.35) compared with women

without breast cancer. The risk was highest in the first 2 years after diagnosis among those who

received adjuvant chemotherapy (Lipscombe 2012). Another Canadian study assessed diabetes

incidence in colorectal cancer (n=39,707) patients. The overall diabetes incidence was 8.7% over

a mean follow-up time of 4.8 years. The overall diabetes incidence was higher in patients with no

metastasis (10.6% versus 8.6%, p<0.01), and lower in patients who received chemotherapy

(8.0% versus 9.0%) (Singh 2014).

Prevalence of diabetes:

In a US cancer registry study, excluding skin and haematologic malignancies, 15,951 cancer

cases were identified, in whom the overall diabetes prevalence was 6.8%. Diabetes was common

among patients with pancreatic (9.8%), colorectal (7.7%), or bladder (7.6%) cancers

(Karlin 2012). Diabetes prevalence in patients with cancer admitted to a cancer hospital in the

United Kingdom was reported to be 11%, and over half of the patients had gastrointestinal tract

primary cancers (Morganstein 2012). However, diabetes prevalence (32.4%) was much higher in

patients with cancer admitted to a Spanish hospital, with a greater prevalence observed in

patients with prostate cancer (Sánchez Peralta 2012). A study of 40 patients with primary

pancreatic cancer in Turkey reported recent-onset diabetes and impaired glucose tolerance in

32.5% and 5% of pancreatic patients, respectively (Cetin 2002).

Mortality of diabetes:

A meta-analysis of 15 studies that reported on postoperative cancer mortality associated with

diabetes reported that pre-existing diabetes conferred a 50% increased risk of mortality in newly

diagnosed patients with cancer after surgery (Barone 2010). Another meta-analysis reported that

patients with breast cancer and diabetes had a significantly higher all-cause mortality risk

(pooled HR 1.49; 95% CI: 1.35-1.65) compared with their nondiabetic counterparts

(Peairs 2011). In a prospective study of participants recruited from German primary care

practices, the incidence of deaths from cancer in patients with Type 2 diabetes (2.6%) was higher

than in those without diabetes (1.2%) (Baur 2011). When investigated by cancer type in a

US registry study, patients with pancreatic cancer who had coexisting diabetes had better overall

survival than those without diabetes (HR=0.60; 95% CI: 0.44-0.80); however, the opposite was

true for diabetic patients with prostate cancer (HR=1.36; 95% CI: 1.05-1.76) (Karlin 2012).


Incidence of CVD:

A nationwide study in Sweden observed a 70% greater overall incidence of coronary heart

disease in patients with cancer compared with the general population without cancer. The IR was


43

highest for leukaemia and cancers of the small intestine, kidney, lung, and liver during the first

6 months of diagnosis (Zöller 2012).

In a large prospective study of patients with breast cancer in Denmark and Sweden, the incidence

ratio of any heart disease among women who did not receive any radiation therapy for

left- versus right-side breast cancer was 1.04 (95% CI: 1.00-1.09). Among women who received

radiation therapy, the incidence ratio for left- versus right-side breast cancer was

1.08 (95% CI: 1.02-1.15) (McGale 2011). In a retrospective study of 271 patients with incident

epithelial ovarian cancer in the United States, 49% experienced comorbid CVD during the study

period (Shinn 2013). Reviews have also reported on the incidence of different types of

cardiovascular morbidity (such as CHF) in relation to specific antineoplastic drugs

(Senkus 2011; Khakoo 2008).

Prevalence of CVD:

Prevalence of comorbid CVD has been reported separately for specific cancer types in different

studies. For instance, according to a US Medicare study of patients with breast cancer aged

66 years and older, the prevalence of CVD at the time of cancer diagnosis was 12.8%

(Patnaik 2011). In a hospital-based study in Italy, of the 189 patients who underwent surgery for

non-small cell lung cancer, 17.5% had concurrent CVD (Pavia 2007). However, a high

prevalence of cardiovascular comorbidity of 52% has been observed among patients with

metastatic colorectal cancer (Overbeek 2012). Finally, in 5,077 patients with prostate cancer in a

US study, 256 had CHF or MI at baseline (Nanda 2009).

Mortality of CVD:

A US Medicare study of patients with breast cancer aged 66 years and older found CVD to be

prevalent in 16.7% of deaths from breast cancer and 59.2% of deaths from other causes

(Patnaik 2011). In a hospital-based study in Italy, of the 189 patients who underwent surgery for

non-small cell lung cancer, 61% with concurrent CVD were alive at 5-year follow up

(Pavia 2007). In a retrospective study of 271 patients with incident epithelial ovarian cancer in

the United States, fewer than 15% of patients died within 1 month of developing a cardiovascular

event (Shinn 2013).

Comorbidity: Renal Failure

Incidence of renal failure:

The incidence of contrast-induced nephropathy after contrast-enhanced computed tomography in

hospitalised patients with cancer was 20% in a Turkish study (Cicin 2014). A nested case-control

analysis involving patients newly diagnosed with prostate cancer using data extracted from the

UK Clinical Practice Research Datalink reported 232 incident cases of acute kidney injury for an

incident rate of 5.5 per 1,000 PY (Lapi 2013).

Prevalence of renal failure:

In the Belgian Renal Insufficiency and Anticancer Medications study, among 1,218 patients with

cancer, the prevalence of elevated serum creatinine (≥1.2 mg/100 mL) was 14.9%, but 64% had


44

a GFR <90 mL/min/1.73 m2 (Janus 2010). Similarly, the Renal Insufficiency and Anticancer

Medications study, a French national observational study of nearly 5,000 patients, observed that

57.4% and 52.9% of patients had abnormal renal function or renal insufficiency when assessed

using Cockcroft-Gault and Modification of Diet in Renal Disease formulae, respectively

(Launay-Vacher 2007). Specifically, among 445 patients with lung cancer in the same study,

62.1% and 55.9% had abnormal renal function using the 2 formulae (Launay-Vacher 2009a);

prevalence of abnormal renal function was 51.8% and 50.8% in 1,898 patients with breast cancer

(Beuzeboc 2012) and 62.6% and 55.9% in 222 patients with prostate cancer

(Launay-Vacher 2009b).

Mortality of renal failure:

In a Belgian retrospective study, among critically ill patients who received RRT for acute renal

failure, those with haematologic malignancies (n=50 of 222) had higher crude intensive care unit

(79.6% versus 55.7%) and in-hospital (83.7% versus 66.1%) mortality rates, and a higher

mortality at 6 months (86% versus 72%) compared with those without haematologic

malignancies. However, after adjustment for severity of illness and duration of hospitalisation

before intensive care unit admission, haematologic malignancy by itself was no longer associated

with higher risk of death (Benoit 2005).

Comorbidity: Cerebrovascular Disease

Incidence of cerebrovascular disease:

In a Swedish study, the observed number of strokes was 1,766 in 25,171 women with breast

cancer, resulting in 12% increased risk (RR=1.12; 95% CI: 1.07-1.17). Most cerebrovascular

events occurred in women aged 70 years and older at the time of breast cancer diagnosis. In

women aged 55 to 69 years and 70 years and older, the risk of stroke was statistically

significantly increased by 11% and 14% respectively, while there was no statistically significant

increased risk of stroke in women younger than 55 years of age at the time of their breast cancer

diagnosis (Nilsson 2005).

A US SEER-Medicare cohort of 6,862 patients with nonmetastatic head and neck cancer

observed a 10-year incidence of cerebrovascular events in 34% in patients treated with

radiotherapy alone, 25% in patients treated with surgery plus radiotherapy, and 26% in patients

treated with surgery alone (Smith 2008). In another study of patients from a US cancer centre, of

195 stroke patients who had stroke diagnosed during 1997 to 2001, 96 patients had confirmed

stroke during the study period, representing 0.12% of all admissions to the cancer centre. Stroke

incidence by specific cancer type was as follows: 30% lung, 9% intracranial, 9% prostate,

4% breast, 6% lymphoma, 6% leukaemia, 6% gynaecologic, 6% bladder, 6% gastroesophageal,

and 20% nonspecified (Cestari 2004).

Prevalence of cerebrovascular disease:

In a Swedish registry-based study, 868 women had a stroke before being diagnosed with breast

cancer during 1970 to 2000 (Nilsson 2005). In a US SEER-Medicare study, the prevalence of


45

cerebrovascular disease was 8% in patients with ovarian cancer compared with 9.8% in women

who were cancer free (Chia 2013).

Mortality of cerebrovascular disease:

A Swedish registry-based study of 25,171 women with breast cancer observed that stroke

contributed to 7% of 12,840 deaths observed during follow up (Nilsson 2005). In a study of

patients from a US cancer centre, the median overall survival was 4.5 months for 96 patients

with a stroke diagnosis; 25% died within 30 days of their stroke (Cestari 2004).

Comorbidity: Myelosuppression/Infection

Incidence of myelosuppression:

In a US retrospective cohort chart review of patients with cancer, the incidence of Grade 3 or 4

myelosuppression was 22% in obese patients and 27% in non-obese patients. Of the patients who

developed myelosuppression, 33% in the obese group and 20% in the non-obese group

experienced myelosuppression on the first cycle of chemotherapy while the majority of

myelosuppression occurred later in the chemotherapy cycles. In patients with lung cancer, the

incidence of Grade 3 or 4 myelosuppression was higher than for rest of the cancer types in the

study (Lopes-Serrao 2011).

Prevalence of myelosuppression:

Findings from a large US study including 387,319 hospitalised elderly patients with

non-haematologic malignancies indicated that among those whose length of stay at the hospital

was more than 10 days, 28.8% had neutropenia and 47.4% had infection (Shayne 2013).

Mortality of myelosuppression:

The same study above reported that, among patients who died, 16.2% had neutropenia and

20.2% had infection (Shayne 2013). Results from 2 systematic reviews on the impact of

chemotherapy-induced myelosuppression on survival demonstrated that among 7 Phase 1 studies

in patients with solid tumours, chemotherapy-related myelosuppression was associated with

reduced mortality (HR=0.69; 95% CI: 0.61-0.77) (Lyman 2013).


Autologous blood donation is a procedure and not a condition; therefore, there are no associated

comorbidities.

Surgery

Comorbidity: Obesity in Elective Orthopaedic Surgery

Incidence of obesity in elective orthopaedic surgery:

There are no data published on the incidence of obesity in elective orthopaedic surgery.


46

Prevalence of obesity in elective orthopaedic surgery:

In a UK study of 385 patients who underwent TKR surgery, the overall prevalence of

pre-operative obesity was 45%, while 15% of knee replacements were in highly obese

(BMI ≥35) patients (Collins 2012). Another study using data from the Clinical Practice Research

Datalink reported a mean BMI (kg/m2) for female THR patients of 29.6 and for male

THR patients of 28.8 (Culliford 2015). In a Norwegian study, increased BMI was strongly

associated with an increased risk of TKR, with an adjusted HR of 6.16 (4.23-8.95) for those with

a BMI >27.3 kg/m2 (Apold 2014). Among US Medicare patients who underwent primary total

knee arthroplasty between 1998 and 2010, 11.4% were obese. The rate of revision surgery within

12 months after primary total knee arthroplasty was significantly increased in obese patients

(adjusted HR=1.19; 95% CI: 1.01-1.39) than in non-obese patients (Bozic 2014). In another

US study conducted using a health maintenance organisation database, obesity was more

prevalent in total knee arthroplasty patients (52%) than total hip arthroplasty patients (36%)

(Namba 2005).

Mortality of obesity in elective orthopaedic surgery:

Mortality after elective orthopaedic surgery in general is not very high. In a prospective matched

study of obese and non-obese patients in the United Kingdom who underwent TKR, no deaths

were observed during the immediate perioperative period or within 3 months of the knee

replacement. However, 1 death each in the obese and non-obese group was observed 3 years

after revision for deep infection (obese patient) and 4 years after the primary surgery for the

non-obese patient (Amin 2006). A US study using Nationwide Inpatient Sample (NIS) data

comparing morbidly obese patients to matched controls reported an in-hospital mortality rate of

0.08% for morbidly obese patients after TKR compared with 0.02% for non-obese patients

(OR: 32; 95% CI: 2.0.-5.2) (D’Apuzzo 2015).

Comorbidity: Osteoarthritis

Incidence of OA:

The incidence of OA is difficult to estimate due to its gradual progressive development and the

problems of definition of new cases. However, it is estimated that for both men and women, the

incidence of OA rises steeply after the age of 50, peaking in the 70- to 79-year-old age group

(Eumusc.net 2014).

A prospective population-based cohort study in Sweden followed 11,026 men and

16,934 women for 11 years. In that study period, 471 individuals had knee OA and

551 individuals had hip OA (Lohmander 2009).

Prevalence of OA:

Prevalence of OA varies based on the age group of the population studied. Data collected as part

of the Global Burden of Disease project (GBD 2010) estimate the standardised prevalence rate of

hip OA per 100 population to be 4.20 in Denmark; 5.12 in Finland; 0.94 in Greece; 20.29 in

Hungary; 1.61 in the 18- to 91-years old age group to 7.70 in the 65- to 99-years old age group in

Italy; 6.80 in the 25- to 99-year-old age group to 51.29 in in the 60- to 89-years old age group in


47

Netherlands; 24.72 to 51.29 in people over 60 years in Spain; 3.88 in Sweden; and 26.28 in those

>60 years old in the United Kingdom.

The standardised prevalence rate of knee OA per 100 population was reported as follows: 3.74 in

Estonia; 6.55 in Greece; 28.30 in Hungary; 29.80 to 43.01 in the elderly in Italy; 6.95 to

43.01, depending on the age group studied, in the Netherlands; 35.12 to 71.10 in people

>60 years old in Italy; 53.87 in Sweden; and 6.50 to 9.84 in the United Kingdom.

In a province-based study in Spain that included 7,577 participants, the derived prevalence of hip

OA and knee OA were approximately 7.4% and 12.2%, respectively. The estimated

appropriateness rate for hip replacement was 37.7% in men and 52.7% in women with OA, with

the same for knee replacement (11.8% in men and 17.9% in women with OA (Quintana 2008).

Mortality of OA:

In a population-based cohort study in the southwest of England, among 1,163 patients with OA,

438 deaths were observed. Patients with OA had 55% excess all-cause mortality compared with

the general population (standardised mortality ratio: 1.55; 95% CI: 1.41-1.70). Excess mortality

was also observed for all disease-specific causes of death but was especially pronounced for

cardiovascular- and dementia-associated mortality (Nüesch 2011).

However, of 1,998 primary THR and TKRs performed for OA in patients aged ≥75 years in a

single institution in Finland, mortality was 0.15% at 30 days, 0.35% at 90 days, 1.60% at 1 year,

7.6% at 3 years, and 16% at 5 years; this was similar following hip and knee replacement,

indicating low postoperative mortality in healthy elderly joint replacement recipients

(Jämsen 2013a). Similarly, a Danish nationwide epidemiologic study to assess mortality for

patients undergoing THR for OA reported 20% lower overall short-term (0-90 days) mortality

(mortality rate ratio: 0.8; 95% CI: 0.7 to 0.9) and 30% lower long-term mortality

(up to 12.7 years) in comparison with general population controls (Pedersen 2011).


Incidence of CVD:

A retrospective nationwide cohort study within the Danish national registries that included

95,227 patients who underwent a primary THR or TKR surgery between January 1998 and

December 2007 observed an absolute 6-week risk of acute MI to be 0.51% in THR patients and

0.21% in TKR patients. The risk of acute MI was substantially increased in the first 2 weeks

after THR (25-fold) and TKR (31-fold) surgery compared with controls (Lalmohamed 2012).

Another Danish study using data covering THRs and TKRs over a 6-year period observed that

0.7% experienced a major adverse cardiovascular event within 30 days after elective TKR or

THR (Thornqvist 2014). A US analysis of hospital discharges from 2008 to 2011 reported the

incidence of in-hospital acute MI was 0.20% after THR or TKR (Menendez 2015). Similarly,

results from a hospital-based study in the United Kingdom that analysed postoperative outcomes

in 2,090 patients admitted with an acute hip fracture over a 4-year period observed that heart

failure (5%) was a common postoperative complication (Roche 2005).


48

In a Canadian study of 1,744 adults with validated OA, 173 (9.9%) participants had a primary

total joint arthroplasty. Of these, 153 participants were successful matched based on propensity

scores with a participant who did not have the procedure. Overall, 111 (36.3%) cardiovascular

events occurred in the matched cohort of 153 pairs, and participants who underwent a total joint

arthroplasty were 44% less likely to have experienced a cardiovascular event (HR=0.56;

95% CI: 0.43-0.74) during follow up (Ravi 2013).

Prevalence of CVD:

In the Danish nationwide cohort study above, the prevalence of ischaemic heart disease and CHF

in THR patients was 12.5% and 7.9%, respectively, and in TKR patients was 11.8% and 5%,

respectively (Lalmohamed 2012). Similarly, in a Finnish registry-based study of THR and TKR

performed for primary OA, the following prevalence of CVDs was reported: 12% coronary heart

disease, 5.4% atrial fibrillation, and 3.5% heart failure for THR recipients, and 12.5% coronary

heart disease, 5.8% atrial fibrillation, and 4.4% heart failure for TKR recipients (Jämsen 2013b).

Another study that included patients in the United Kingdom reported 24.8% of TKR patients in

the United Kingdom also had heart disease (Oleske 2014).

Mortality of CVD:

The Thornqvist study cited above also reported a 30-day mortality rate from cardiovascular

causes of 0.2% and a 1-year mortality rate from cardiovascular causes of 0.8% after TKR or

THR surgery (Thornqvist 2014).

Findings from a hospital-based study in the United Kingdom that analysed postoperative

outcomes in 2,090 patients admitted with an acute hip fracture over a 4-year period observed

mortality rates of 9.6% at 30 days and 33% at 1 year. In patients who developed postoperative

heart failure (5%), mortality was 65% at 30 days, and of these patients, 92% were dead within

1 year (Roche 2005). In another UK study of 467 patients who underwent hip fracture surgery at

a hospital, acute coronary syndrome was the cause of death in 31.4% of the 35 patients who died

(Khan 2013).



There are no data published on the incidence of hypertension in elective orthopaedic surgery.


Data from a Finnish registry-based study that included 43,747 THR recipients and 53,007 TKR

recipients performed for OA reported hypertension prevalence to be 17.7% in THR recipients

and 20.8% in TKR recipients (Jämsen 2013b). Another study that included patients in the United

Kingdom reported 49.3% of TKR patients also had hypertension (Oleske 2014).

In a large US study of 3,960 same-day, 172-Staged 0-3, and 1,533-Staged 3-12 bilateral total

knee arthroplasties (TKAs), the prevalence of hypertension in the 3 groups were 50.8%, 57%,

and 66.8%, respectively, while the rates for pulmonary hypertension was 1.6%, 2.9%, and 2.6%,


49

respectively (Poultsides 2014). Another US study compared the way in which the National

Hospital Discharge Survey (NHDS) and the NIS reported data on THR. In this study, the NHDS

reported that 54% of THR patients had hypertension as a comorbid condition and the NIS

reported 58% (Bekkers 2014).


In the study by Poultsides et al above (Poultsides 2014), hypertension was not associated with

major morbidity and mortality in patients who underwent same-day bilateral TKAs, but patients

with pulmonary hypertension had over 2 times the risk (OR=2.34; 95% CI: 1.08-5.08) compared

with those who did not have the comorbidity. Another similar US study that used the largest

inpatient database to identify total knee athroplasty and total hip arthroplasty entries observed

that patients with pulmonary hypertension undergoing total hip arthroplasty experienced an

approximately 4-fold increased adjusted risk of mortality (2.4% versus 0.6%), and those

undergoing total knee athroplasty had a 4.5-fold increased adjusted risk of mortality (0.9%

versus 0.2%) compared with patients who did not have pulmonary hypertension (Memtsoudis

2010).



Incidence of CVD:

Cardiovascular disease is often the most frequently reported comorbidity in MDS patients. In a

US study of 512 MDS patients, of the 303 (59.2%) patients who had no history of cardiac

disease, 188 (62%) patients developed cardiac disease during a 3-year follow up, compared with

54.5% of the Medicare population. Age-adjusted analyses revealed that MDS was associated

with a more than 2-fold increased risk of cardiac-related events (Goldberg 2010).

Prevalence of CVD:

In an Austrian MDS cohort of 616 patients, the prevalence of cardiac disease was 25.2% (n=155)

and CVD was 28.4% (n=175). Specifically, at baseline, 18.3% had coronary heart disease,

cardiac insufficiency, or MI, 9.3% had arrhythmia, and 3.4% had valvular heart disease

(Bammer 2014). Another cohort of 840 MDS patients in an Italian trial observed that cardiac

disease was the most frequently observed (25%) comorbidity. The frequency of individual

cardiac events was as follows: arrhythmia, 7%; heart valve disease, 2%; coronary artery disease

of MI, 8%; and CHF or ejection fraction <50%, 19%. This study also included a validation

cohort of 504 MDS patients from Germany, in who the prevalence of cardiac diseases was higher

at 39% (Della Porta 2011). This was also observed in another Italian study of 418 patients with a

prevalence of cardiac disease of 28.4%; specifically, 10% had infarction, 21% had coronary heart

disease without infarction, 50% had cardiomyopathy, 19% had cardiac valve disease, ad 50%

had arrhythmia (Breccia 2011). A US study of 512 elderly MDS patients observed a prevalence

of 19.3% for cardiac events, 48.2% for MIs, 51.2% for CHF, and 51.2% for arrhythmias.

Overall, 73.2% of MDS patients experienced any cardiac events, which was significantly higher

that 54.5% of the Medicare population (Goldberg 2010).


50

Mortality of CVD:

Data from a cohort of 840 MDS patients in an Italian trial observed that 63% of non-leukemic

deaths in these patients was due to cardiac failure, and cardiac disease was independently related

to the risk of non-leukemic death (HR: 3.57) in a multivariate analysis (Della Porta 2011).

Similarly, in a US study of 1,708 elderly MDS patients, those with CHF (20.8%) had a 35%

increased risk of mortality (HR: 1.35, 95% CI: 1.16-1.57) than patients without the condition

(Wang 2009).

Comorbidity: Diabetes

Incidence of diabetes:

Diabetes has also been frequently observed in MDS patients in the literature. In a US study of

512 MDS patients, of the 380 patients who had no history of diabetes, 82 (21.6%) developed

diabetes during a 3-year follow up (Goldberg 2010).

Prevalence of diabetes:

In an Austrian MDS cohort of 616 patients, the prevalence of diabetes was 12.2% (n=75)

(Bammer 2014). Another cohort of 840 MDS patients in an Italian study observed that 11% had

diabetes (Della Porta 2011), while an Italian study of 418 patients observed diabetes in 18.7% of

patients, with organ damage in 20 patients (Breccia, 2011). In a study of 171 patients from the

Dusseldorf MDS Registry in Germany, diabetes was the most frequent comorbidity observed in

21 patients (Zipperer 2009). A US study of 1,708 MDS patients observed that 21.8% had

diabetes and 5.9% had diabetes with sequelae (Wang 2009). Another US study of

512 MDS patients observed diabetes prevalence of 40% in these patients, higher compared with

33.1% in the Medicare population (Goldberg 2010).

Mortality of diabetes:

Data from a cohort of 840 MDS patients in an Italian study observed that diabetes was not

independently related to the risk of non-leukaemic death in a multivariate analysis

(Della Porta 2011). Similarly, in a US study of 1,708 elderly MDS patients, diabetes did not

appear to affect survival (Wang 2009).



Incidence data on hypertension in MDS patients is not available as data on hypertension are

mostly available as case reports and small series.


In a US study of 600 MDS patients, approximately 55% of patients were diagnosed with a

disorder of the cardiovascular system, with hypertension being the most common comorbidity at

37% (Naqvi 2011). A small retrospective chart review of 26 patients who had received a

diagnosis of both chronic myeloid disorders and pulmonary hypertension observed 2 patients had


51

MDS (Dingli 2001). Another study of 88 patients observed hypertension to be present in 45.4%

of patients (De Roos 2010).


Not described.

Comorbidity: Cerebrovascular Disease

Incidence of cerebrovascular disease:

Not described.

Prevalence of cerebrovascular diseases:

In an Austrian MDS cohort of 616 patients, the prevalence of cerebrovascular disease was 7.1%

(n=44) (Bammer 2014). Another cohort of 840 MDS patients in an Italian study observed that

5% of patients had cerebrovascular disease (Della Porta 2011). A US study of

1,708 MDS patients observed that 8% had cerebrovascular disease (Wang 2009).

Mortality of cerebrovascular diseases:

Data from a cohort of 840 MDS patients in an Italian study observed that cerebrovascular disease

was not independently related to risk of non-leukaemic death in a multivariate analysis

(Della Porta 2011). Similarly, in a US study of 1,708 elderly MDS patients, cerebrovascular

disease, which was present in 8% of patients, did not appear to affect survival (Wang 2009).

Cormorbidity: Prior Malignancies

Incidence of prior malignancies:

No incidence estimates can be computed, as by definition, prior malignancies will have occurred

before MDS diagnosis.

Prevalence of prior malignancies:

In an Austrian MDS cohort of 616 patients, the prevalence of prior tumour was 9.9% (n=61)

(Bammer 2014). Another cohort of 840 MDS patients in an Italian study observed that 10% had

solid tumours at any time point in the patient’s history, excluding non-melanoma skin cancer

(Della Porta 2011), while an Italian study of 418 patients observed tumours in 6% of patients

(Breccia 2011). Yet another study of 11 patients from the Dusseldorf MDS Registry in Germany

observed 9 patients with a solid tumour (Zipperer 2009).

Mortality of prior malignancies:

Data from a cohort of 840 MDS patients in an Italian study observed that solid tumour was

independently related to risk of non-leukaemic death (HR: 2.61) in a multivariable analysis

(Della Porta 2011). However, in a US study of 1,708 elderly MDS patients, the most frequently

reported cause of death was neoplasm, accounting for 888 (56.6%) deaths, and among patients

who died from neoplasm, 42.5% were reported to have died from MDS and 38.4% died from

leukaemia (Wang 2009).


52



Module SII: Nonclinical Part of the Safety Specification






Data lock point for this module 30 June 2015





53

Key Safety Findings From Nonclinical Studies

Key Safety Findings(from nonclinical studies) Relevance to Human Usage

Toxicity findings include:

Single & repeat-dose toxicity

No acute toxicities were observed at single epoetin alfa doses up to 20,000 units/kg in mice and rats (oral, IM, and IV) or in dogs (IV). Findings observed after single-dose administration of epoetin alfa included moderate increases in erythropoiesis in bone marrow, mucoid faeces, and slight elevations of lactate dehydrogenase in dogs at 20,000 units/kg, as well as changes in haematology parameters due to the pharmacological activity of epoetin alfa(eg, such as increases in HCT, HGB, and reticulocyte counts), which were observed in both the single-dose and in all repeated-dose toxicity studies.

Repeated-dose studies of up to 13 weeks were conducted in monkeys (SC, IV), while studies of up to 52-weeks duration were conducted in rats (IP) and dogs (SC, IV). The major toxicology findings observed following repeated epoetin alfa administration to animals were related to polycythaemia that developed as a result of prolonged overstimulation of RBC production. Overstimulation of RBC production resulted in premature deaths in rats and dogs in the chronic studies, with mortality rates approaching 80% in rats at 250 units/kg/day and 50% in dogs at doses ≥100 units/kg/day. As a result of high systemic epoetin alfaconcentrations, extramedullary haematopoiesis was seen in spleen and liver, and depletion of iron stores and myelofibrosis was seen in the bone marrow in rats and dogs. The increased severity with time and/or dose suggests a potential for bone marrow toxicity resulting from sustained or marked stimulation of erythropoiesis.

In repeated-dose toxicologic studies in dogs and rats, but not in monkeys, epoetin alfa therapy was associated with subclinical bone marrow fibrosis. Bone marrow fibrosis is a known complication of CRF in humans and may be related to secondary hyperparathyroidism or unknown factors. The incidence of bone marrow fibrosis was not increased in a study of patients on haemodialysis who were treated with epoetin alfa for 3 years compared with a matched control group of dialysis patients who had not been treated with epoetin alfa (SmPC Section 5.3).

An increased incidence of TVEs has been observed in patients receiving ESAs (SmPC Sections 4.4 and 4.8). These include venous and arterial thromboses and embolism (including some with fatal outcomes), such as DVT, pulmonary emboli, retinal thrombosis, and MI. Additionally, cerebrovascular accidents (including cerebral infarction, cerebral haemorrhage, and transient ischaemic attacks) have been reported.


54



Changes in platelet count seen in rats and dogs suggest a role for erythropoietin in the terminal stage of megakaryocyte maturation leading to platelet release. A shift toward the production of proerythroblasts at the expense of megakaryocytes may occur with continued dosing, the timing of the shift being dependent on dosage. These data suggest that,although changes in platelet counts may occur, the risk of these changes resulting in thrombosis appeared small.

Kidney and lung thrombi were observed at the higher epoetin alfa dose levels in rats dosed for 52 weeks, but thrombi were not observed in the dog or monkey studies.

Toxicology studies were not conducted in renally impaired animals.

Reproductive toxicity

The administration of epoetin alfa does not impair fertility in rats.

There is no relevance to humans.

Developmental toxicity

The administration of epoetin alfa does not result in embryo-foetal toxicity in rats or rabbits. A peri-and postnatal developmental toxicology study in rats showed no effect on maturation of offspring.

In animal studies, epoetin alfa has been shown to decrease foetal body weight, delay ossification, and increase foetal mortality when given in weekly doses of approximately 20 times the recommended human weekly dose.

Findings from repeated-dose toxicology studies in juvenile dogs and monkeys were consistent with those seen in adult animals.

Findings in the toxicology studies were interpreted as being secondary to decreased maternal body weight gain when given in weekly doses of approximately 20 times the recommended human dose; therefore, the significance to humans is unknown when given at therapeutic dose levels. Findings in animal studies do not represent a developmental toxicity of the drug, but rather, are due to polycythaemia seen in the dams.


55



Hepatotoxicity

Systemic toxicity studies did not show hepatotoxicity and therefore no further hepatoxicity studies were conducted.

There are no nonclinical data to indicate that there would be any hepatotoxicity in humans.

Genotoxicity

Epoetin alfa does not induce bacterial gene mutation (Ames test), chromosomal aberrations in mammalian cells, gene mutation at the hypoxanthine-guanine phosphoriosyltransferase locus, nor micronuclei in mice administered IV doses up to 500,000 units/kg.

These studies demonstrate that epoetin alfa has low potential to inflict genetic damage when administered to humans.

Carcinogenicity

As EPREX is a biotechnology-derived pharmaceutical product, rodent carcinogenicity studies were not conducted, consistent with ICH S6(R1) guidance.

Long-term carcinogenicity studies have not been conducted. Conflicting reports in the literature, based on in vitro findings from human tumour samples, suggest erythropoietins may play a role as tumour proliferators. This is of uncertain significance in the clinical situation. Nonclinical studies have shown that treatment with ESAs does not enhance tumour progression directly or through enhanced angiogenesis/vasculogenesis.

The risk of tumour initiation or proliferation of established tumours is unclear from preclinical data. Disease progression has been determined to be an important potential risk for the product. A clinical trial is ongoing (EPO-ANE-3010) to assess disease progression in anaemic patients with metastatic breast cancer receiving EPREX and chemotherapy. Refer to SVII.3 for additional details regarding Trial EPO-ANE-3010.

General safety pharmacology findings:

Cardiovascular (including potential for QT interval prolongation)


56



In cardiovascular assessments in guinea pigs and dogs, vehicle and epoetin alfa at a concentration of 1,000 units/mL suppressed contractile force or contraction rate in the isolated guinea pig atria. In conscious dogs, there were transient increases in heart rate at 20 and 2,000 units/kg epoetin alfa IV (transient and slightly decreased at 200 unit/kg) and slight decreases in mean blood pressure at 200 and 2,000 units/kg epoetin alfa IV. Slightly increased R-wave heights and R-R intervals were observed in all dose groups.

Nonclinical in vitro studies were conducted up to 1,000 IU/mL, which is approximately 1,000 times the achieved maximum plasma exposure of epoetin alfa when administered at 40,000 IU/mL once per week.Therefore, there is no anticipated risk of QT prolongation to patients.

Nervous system

Epoetin alfa administered to mice and rats via IP doses of 450 and 1,500 units/kg TIW for 3 weeks did not affect brain excitability in mice, did not alter water content or electrolyte distribution of the cerebral cortex, cerebellum, or subcortex in rats, and did not affect electrolyte contributions in rat plasma or cerebrospinal fluid. In mice, rats, and rabbits administered IV doses of 20, 200, or 2,000 units/kg, epoetin alfa did not have significant effects on general behaviour, motor coordination, analgesia, hexobarbital-induced sleeping time, anticonvulsion, and spontaneous electroencephalogram led from the amygdaloid, hippocampus, and the cortices of motor, sensory, and visual areas, and spinal reflex. A decrease in body temperature was seen in rats administered 2,000 units/kg IV epoetin alfa; no other evidence of depression or stimulation of the central nervous system was noted at the same dose.

There are no risks identified in nonclinical studies that haven’t been adequately addressed in clinical trials.

Other - Immunogenicity

Antibodies to erythropoietin can be generated in preclinical species. In repeated-dose toxicology studies, Ab titres were of low frequency, but the Ab response can be stimulated by the use of adjuvants and an aggressive immunisation schedule.

There are no risks identified in nonclinical studies that haven’t been adequately addressed in clinical trials. The risk of PRCA was first identified in postauthorisation usage and is considered an important identified risk and is described in detail in Module SVII.3 of this RMP.


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Mechanisms for drug interactions

None Not applicable

Other toxicity-related information or data

None Not applicable

Ab=antibody; CRF=chronic renal failure; DVT=deep vein thrombosis; ESA=erythropoiesis-stimulating agent; HCT=haematocrit; HGB=haemoglobin; ICH=International Council for Harmonisation; IM=intramuscular; IP=intraperitoneal; IV=intravenous; MI=myocardial infarction; PRCA=pure red cell aplasia; RBC=red blood cell, RMP= risk management plan; SC=subcutaneous; TIW=3 times per week; TVE=thrombotic vascular event

SII. Conclusions on Nonclinical Data

No nonclinical safety signals have been detected that are relevant for the clinical setting because

most derive from polycythaemia (exaggerated pharmacology of epoetin alfa) or an immune

response due to epoetin alfa being foreign in animals.

Nonclinical Safety Concerns

Important identified risks

None Not applicable

Important potential risks

None Not applicable

Missing information

None Not applicable


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Module SIII: Clinical Trial Exposure











59

SIII.1. Brief Overview of Development

EPREX solution for injection is Janssen-Cilag’s proprietary medicinal product containing the

active substance epoetin alfa, a purified glycoprotein hormone of recombinant DNA origin that

stimulates erythropoiesis (recombinant human erythropoietin [r-HuEPO]). EPREX is formulated

as a sterile, colourless solution for IV and SC administration. The initial dossier to the EU,

submitted as Concertation Procedure No. 3 (Directive 87/22/EEC), received a positive opinion

from the Committee for Medicinal Products for Human Use (CHMP) in June 1988 for the use of

EPREX in the treatment of adult patients with CRF on haemodialysis (IV route of

administration). EPREX solution for injection is marketed as prefilled syringes under several

trade names including EPREX throughout most of the world, ERYPO in Germany and Austria,

and PROCRIT® in the United States.

The use of EPREX is currently approved in 97 countries worldwide for the treatment of anaemia

in patients with CRF (dialysis and predialysis) and supportive anaemia care and reduction of

transfusion requirements in adults with cancer receiving chemotherapy (Annex 3). It has also

been approved in several countries as a facilitator of ABD and in several countries to reduce

allogeneic blood requirements in the perisurgical setting.

Since the original 1988 EU approval, the following extensions to the therapeutic use of EPREX

have been granted in the EU:

Adult patients with CRF with renal insufficiency not yet undergoing dialysis; IV and SCroutes of administration (July 1990)

Adult patients with CRF on haemodialysis; SC route of administration (December 1991)

Adult patients with CRF on chronic ambulatory peritoneal dialysis; SC route ofadministration (December 1992)

Paediatric patients with CRF on haemodialysis; IV route of administration (March 1993)

Adult patients with cancer receiving platinum-containing chemotherapy; SC route ofadministration (May 1994)

Patients donating autologous blood prior to surgery; IV route of administration (June 1994)

Patients undergoing elective, orthopaedic surgery; SC route of administration(February 1998)

Chronic Renal Failure Indication

Data from 30 clinical trials with patient-level data (n=7,656 patients treated with EPREX) in the

CRF indication are included in the analyses of exposure and risk in the following sections. More

studies have been conducted over the years to support label changes and new dosage forms that

form the basis of the efficacy and safety of EPREX in this patient population.


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Cancer Indication

Data from 46 clinical trials with patient-level data (n=5,827 patients treated with EPREX) in the

cancer indication are included in the analyses of exposure and risk in the following sections. As

with the CRF indication, more studies have been conducted over the years to support label

changes and new dosage forms that form the basis of the efficacy and safety of EPREX in this

patient population.

In the following exposure tables, the cancer indication is designated oncology.

Autologous Blood Donation Indication

Seven clinical trials that enroled a total of 644 patients (242 treated with placebo and 402 with

epoetin alfa) were conducted to form the basis for evaluation of efficacy and safety of epoetin

alfa in increasing the yield of autologous blood in patients participating in an ABD programme

before elective surgery.

Surgery Indication

The efficacy and safety of epoetin alfa in patients undergoing orthopaedic surgery was

demonstrated in 11 clinical trials. A total of 2,940 patients undergoing orthopaedic surgery were

evaluated. Most patients were treated for 10 days to 3 weeks before elective surgery.

Although epoetin alfa is approved for use in conjunction with elective orthopaedic surgery,

Trial H87-083, which enroled 182 patients, was conducted in patients undergoing coronary

artery bypass graft surgery (Annex 4).

Data from 8 trials with patient-level data are included in the analyses of exposure and risk in the

following sections.

MDS Population

Two randomised, double-blind, placebo-controlled clinical trials were conducted to form the

basis for the evaluation of efficacy and safety of epoetin alfa in the treatment of anaemic patients

with MDS. Trial EPO-ANE-3018 was conducted to demonstrate that epoetin alfa treatment

reduces the proportion of anaemic patients with IPSS low- or intermediate-1 risk MDS who

require any transfusion, compared with placebo, through Week 48. Due to poor patient

enrolment, the study was terminated early. Therefore, the total final enrolment was 25 patients,

with 8 patients assigned to the epoetin alfa 40,000 IU group, 9 patients to the epoetin alfa

80,000 IU group, and 9 patients to the placebo group. Trial EPOANE3021 was conducted to

demonstrate the effectiveness of epoetin alfa in inducing and maintaining erythroid response,

significantly reducing the percentage of patients requiring transfusion, and prolonging the time to

first RBC transfusion in patients with IPSS low- or intermediate-1 risk MDS. A total of

130 patients in Europe were randomised, with 85 patients assigned to the epoetin alfa group and

45 patients assigned to the placebo group.


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SIII.2. Clinical Trial Exposure

The clinical trial database from which information is summarised in this document is limited to

the clinical trials for which patient-level data are available. As the start of the clinical trial

programme for EPREX dates back to the mid-1980s, available data are presented below. The

following sections describe the overall clinical trial programme with a data cutoff date of

30 June 2015, with Tables 1 to 20 summarising available patient-level data. This database

includes 93 trials that enroled over 21,000 patients, of whom >70% (15,339 patients) were

exposed to epoetin alfa.

Exposure in Randomised Controlled Clinical Trials

Tabular summaries of completed randomised, controlled epoetin alfa clinical trials are provided

in Annex 4 for the CRF, cancer, ABD, surgery, and MDS indications.

Exposure to EPREX in randomised, controlled clinical trials for which patient-level data are

available, is summarised in Tables 1 through 10 by duration, dose, age and sex, race, and

baseline hepatic and renal status (renal status only for the cancer, ABD, surgery, and MDS

indications).

In the randomised, controlled trials population of 7,595 EPREX-treated patients:

There were 33,583.7 person-months exposure to EPREX (Tables 1 and 2)

A total of 2,361 (31%) were men and 5,234 (69%) patients were women (Tables 5 and 6)

A total of 2,524 (33%) patients were 65 years of age or older, while 781 (10%) patients were 75 years of age or older (Tables 5 and 6)

A majority of patients (5,169 [68%]) were White, while 353 (5%) patients were Black, and 528 patients (7%) were Asian, Hispanic or Latino, American Indian or Alaska Native, or Other (Tables 7 and 8); data on ethnic and racial origin were missing for 1,545 (20%) patients

A total of 4,920 (65%) of the 7,538 patients in the cancer, ABD, surgery, or MDS trials captured in the laboratory database had mild (creatinine clearance [CRCL] >50 to <80 mL/min; n=1,910), moderate (CRCL 30 to <50 mL/min; n=565), or severe (CRCL 30 mL/min; n=60) renal impairment at baseline (Tables 9 and 10); CRCL data at baseline were missing or noted as normal in the database for 2,385 patients (Note: only trials associated with the cancer, ABD, surgery, and MDS indications were included in this evaluation because CRF was evaluated as a separate indication by itself.)


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Table 1 : Exposure by Duration; All Randomised Controlled Clinical TrialsINDICATION: CHRONIC RENAL FAILURE - DIALYSIS

Duration of Exposure Persons (N=97) Person-months Cumulative up to 1 month 5 2.33Cumulative up to 3 months 25 41.1Cumulative up to 6 months 33 79.84Cumulative up to 9 months 97 465.38Cumulative up to 12 months 97 465.38Cumulative up to 18 months 97 465.38Cumulative up to 24 months 97 465.38Chronic Renal Failure – Dialysis Trials: EP86-001 (CEO-C01), EP86-004

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INDICATION: CHRONIC RENAL FAILURE - PREDIALYSISDuration of Exposure Persons (N=464) Person-months Cumulative up to 1 month 57 31.54Cumulative up to 3 months 227 339.61Cumulative up to 6 months 335 867.38Cumulative up to 9 months 343 926.85Cumulative up to 12 months 358 1091.48Cumulative up to 18 months 384 1461.55Cumulative up to 24 months 443 2813.57Cumulative up to 36 months 459 3203.81Cumulative up to 48 months 463 3385.95Missing 1 .

Chronic Renal Failure – Predialysis Trials: EPO-AUS-14, EPO-CAN-10, EPO-ITA-7, EPOCKD2002, G86-011, H87-054

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INDICATION: ONCOLOGYDuration of Exposure Persons (N=5323) Person-months Cumulative up to 1 month 608 195.42Cumulative up to 3 months 2221 3773.04Cumulative up to 6 months 4205 12126.16Cumulative up to 9 months 4533 14452.93Cumulative up to 12 months 4757 16907.93Cumulative up to 18 months 5082 21239.29Cumulative up to 24 months 5189 23440.69Cumulative up to 36 months 5270 25744.23Cumulative up to 48 months 5306 27228.81Cumulative up to 60 months 5312 27563.1Cumulative up to 72 months 5317 27897.43Cumulative up to 84 months 5318 27972.7Missing 5 .

Oncology Trials: CISPLATIN (I88-036, OEO-U24 and OEO-U25), NON-CHEMOTHERAPY (H87-032, OEO-U20 and OEOU21), NON-CISPLATIN (I88-037, OEO-U22 and OEO-U23), AGO/NOGGO (EPO-GER-8), EP92-002, EPO-CAN-15, EPO-CAN-17, EPO-CAN-20, EPO-CAN-203, EPO-CAN-303, EPO-GBR-4, EPO-GBR-7, EPO-GER-20, EPO-GER-22, EPO-GOG-191, EPO-INT-1 (2574-P-416), EPO-INT-10 (EPO-C111-457), EPO-INT-2 (CC2574-P-467), EPO-INT-3 (2574-P-034), EPO-INT-45, EPO-INT-47, EPO-INT-49, EPO-INT-50, EPO-INT-51 (EPO-CA-484), EPO-INT-76 (EPO-CA-489), EPO-J89-040 (J89-040), EPO-N93-004 (N93-004), EPO-P-169 (2574-P-169), EPO-P-174 (CC2574-P-174), MOEBUS, OBE/EPO-INT-03, PR00-03-006, PR00-27-005, PR98-27-008, PR99-11-034/044, PRI/EPO-NED-17, RTOG/PR99-03-046 (PR99-03-046), EPO-ANE-3010, EPO-CAN-29

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INDICATION: AUTOLOGOUS BLOOD DONATIONDuration of Exposure Persons (N=402) Person-months Cumulative up to 1 month 316 199.49Cumulative up to 3 months 389 311.36Cumulative up to 6 months 399 349.6Cumulative up to 9 months 400 356.04Cumulative up to 12 months 400 356.04Cumulative up to 18 months 400 356.04Cumulative up to 24 months 400 356.04Missing 2 .

ABD Trials: CC 2574-P-159, CC 2574-P-165, CC 2574-P-166, H87-017, H87-036, I88-027, I88-058

[TSUB01D.rtf] [JNJ-7472179\Z_RMP\RMP_2015\RE_RMP_2015_EU\tsub01d.sas] 09OCT2015, 14:55

INDICATION: SURGERYDuration of Exposure Persons (N=1207) Person-months Cumulative up to 1 month 1106 638.32Cumulative up to 3 months 1164 718.75Cumulative up to 6 months 1166 726.05Cumulative up to 9 months 1166 726.05Cumulative up to 12 months 1166 726.05Cumulative up to 18 months 1166 726.05Cumulative up to 24 months 1166 726.05Missing 41 .

Surgery Trials: EPO-APO2-474, EPO-INT-34 (EPO-AP02-478), CEO-C04, H87-083, J89-001, M92-011, PR97-19-002 (spine)

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INDICATION: MDSDuration of Exposure Persons (N=102) Person-months Cumulative up to 1 month 6 2.37Cumulative up to 3 months 18 27.53Cumulative up to 6 months 60 247.39Cumulative up to 9 months 67 297.3Cumulative up to 12 months 102 677.59Cumulative up to 18 months 102 677.59Cumulative up to 24 months 102 677.59

MDS Trials: EPO-ANE-3018 and EPOANE3021

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Table 2:Exposure by Duration (Totals); All Randomised Controlled Clinical TrialsINDICATION: ALL

Duration of Exposure Persons (N=7595) Person-months Cumulative up to 1 month 2098 1069.47Cumulative up to 3 months 4044 5211.4Cumulative up to 6 months 6198 14396.42Cumulative up to 9 months 6606 17224.54Cumulative up to 12 months 6880 20224.46Cumulative up to 18 months 7231 24925.9Cumulative up to 24 months 7397 28479.31Cumulative up to 36 months 7494 31173.09Cumulative up to 48 months 7534 32839.82Cumulative up to 60 months 7540 33174.11Cumulative up to 72 months 7545 33508.44Cumulative up to 84 months 7546 33583.7Missing 49 .Chronic Renal Failure – Dialysis Trials: EP86-001 (CEO-C01), EP86-004Chronic Renal Failure – Predialysis Trials: EPO-AUS-14, EPO-CAN-10, EPO-ITA-7, EPOCKD2002, G86-011, H87-054.Oncology Trials: CISPLATIN (I88-036, OEO-U24 and OEO-U25), NON-CHEMOTHERAPY (H87-032, OEO-U20 and OEOU21), NON-CISPLATIN (I88-037, OEO-U22 and OEO-U23), AGO/NOGGO (EPO-GER-8), EP92-002, EPO-CAN-15, EPO-CAN-17, EPO-CAN-20, EPO-CAN-203, EPO-CAN-303, EPO-GBR-4, EPO-GBR-7, EPO-GER-20, EPO-GER-22, EPO-GOG-191, EPO-INT-1 (2574-P-416), EPO-INT-10 (EPO-C111-457), EPO-INT-2 (CC2574-P-467), EPO-INT-3 (2574-P-034), EPO-INT-45, EPO-INT-47, EPO-INT-49, EPO-INT-50, EPO-INT-51 (EPO-CA-484), EPO-INT-76 (EPO-CA-489), EPO-J89-040 (J89-040), EPO-N93-004 (N93-004), EPO-P-169 (2574-P-169), EPO-P-174 (CC2574-P-174), MOEBUS, OBE/EPO-INT-03, PR00-03-006, PR00-27-005, PR98-27-008, PR99-11-034/044, PRI/EPO-NED-17, RTOG/PR99-03-046 (PR99-03-046), EPO-CAN-29, EPO-ANE-3010ABD Trials: CC 2574-P-159, CC 2574-P-165, CC 2574-P-166, H87-017, H87-036, I88-027, I88-058Surgery Trials: EPO-APO2-474, EPO-INT-34 (EPO-AP02-478), CEO-C04, H87-083, J89-001, M92-011, PR97-19-002 (spine)MDS Trials: EPO-ANE-3018 and EPOANE3021

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Table 3:Exposure by Dose; All Randomised Controlled Clinical TrialsINDICATION: CHRONIC RENAL FAILURE - DIALYSIS

Initial dose level Persons (N=97) Person-months 10-50 IU/kg QW 6 10.7151-200 IU/kg QW 13 21.1951-100 IU/kg TIW 78 433.48Total 97 465.38QW=once weekly; TIW=3 times a weekChronic Renal Failure – Dialysis Trials: EP86-001 (CEO-C01), EP86-004.


INDICATION: CHRONIC RENAL FAILURE - PREDIALYSISInitial dose level Persons (N=464) Person-months 1-50 IU/kg TIW 28 51.6151-100 IU/kg TIW 72 117.22101-300 IU/kg TIW 30 42.151,001-5,000 IU QW 211 2680.3110,001-20,000 IU QW 1 13.4710,000-20,000 IU Q2W 116 469.03Missing 6 12.16Total 464 3385.95QW=once weekly; Q2W=once every 2 weeks; TIW=3 times a weekNOTE: One of the 464 patients is missing exposure data and is not included in the calculation of person-months.Chronic Renal Failure – Predialysis Trials: EPO-AUS-14, EPO-CAN-10, EPO-ITA-7, EPOCKD2002, G86-011, H87-054.


INDICATION: ONCOLOGYInitial dose level Persons (N=5323) Person-months 600 IU/kg QW 228 912.36100 IU/kg TIW 65 98.76150 IU/kg TIW 1367 4442.12300 IU/kg TIW 124 490.1840,000 IU QW 2437 18699.9360,000-80,000 IU Q2W 7 26.74120,000 IU Q3W 4 13.344,000-5,000 IU TIW 125 230.3110,000 IU TIW 964 3057.18Missing 2 1.77Total 5323 27972.7QW=once weekly, Q2W=once every 2 weeks; Q3W=once every 3 weeks; TIW=3 times a weekNOTE: Five of the 5,323 patients are missing exposure data and are not included in the calculation of person-months.Oncology Trials: CISPLATIN (I88-036, OEO-U24 and OEO-U25), NON-CHEMOTHERAPY (H87-032, OEO-U20 and OEOU21), NON-CISPLATIN (I88-037, OEO-U22 and OEO-U23), AGO/NOGGO (EPO-GER-8), EP92-002, EPO-CAN-15, EPO-CAN-17, EPO-CAN-20, EPO-CAN-203, EPO-CAN-303, EPO-GBR-4, EPO-GBR-7, EPO-GER-20, EPO-GER-22, EPO-GOG-191, EPO-INT-1 (2574-P-416), EPO-INT-10 (EPO-C111-457), EPO-INT-2 (CC2574-P-467), EPO-INT-3 (2574-P-034), EPO-INT-45, EPO-INT-47, EPO-INT-49, EPO-INT-50, EPO-INT-51 (EPO-CA-484), EPO-INT-76 (EPO-CA-489), EPO-J89-040 (J89-040), EPO-N93-004 (N93-004), EPO-P-169 (2574-P-169), EPO-P-174 (CC2574-P-174), MOEBUS, OBE/EPO-INT-03, PR00-03-006, PR00-27-005, PR98-27-008, PR99-11-034/044, PRI/EPO-NED-17, RTOG/PR99-03-046 (PR99-03-046), EPO-ANE-3010, EPO-CAN-29



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INDICATION: AUTOLOGOUS BLOOD DONATIONInitial dose level Persons (N=402) Person-months Dose level 150 IU/kg BIW 29 16.76Dose level 300 IU/kg BIW 53 32.59Dose level 600 IU/kg BIW 177 105.4Dose level 300 IU/kg TIW 71 88.71Dose level 600 IU/kg TIW 72 112.59Total 402 356.04BIW=2 times a week; TIW=3 times a weekNOTE: Two women (1 in the 18- to 39-year age group and 1 in the 50- to 59-year age group) are missing exposure data and are not included in the calculation of person-months.ABD Trials: CC 2574-P-159, CC 2574-P-165, CC 2574-P-166, H87-017, H87-036, I88-027, I88-058


INDICATION: SURGERYInitial dose level Persons (N=1207) Person-months 100 IU/kg QD 172 82.33150 IU/kg QD 63 16.46300 IU/kg QD 365 239.44600 IU/kg QW 341 228.1440,000 IU QW 241 159.67Missing 25 .Total 1207 726.05QD=once daily; QW=once weeklyNOTE: Forty-one of the 1,207 patients are missing exposure data and are not included in the calculation of person-months.Surgery Trials: EPO-APO2-474, EPO-INT-34 (EPO-AP02-478), CEO-C04, H87-083, J89-001, M92-011, PR97-19-002 (spine)


INDICATION: MDSInitial dose level Persons (N=102) Person-months 450 IU/kg QW 85 603.740,000 IU QW 8 23.3980,000 IU QW 9 50.5Total 102 677.59MDS=myelodysplastic syndrome; QW=once weeklyMDS Trials: EPO-ANE-3018 and EPOANE3021



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Table 4:Exposure by Dose (Totals); All Randomised Controlled Clinical TrialsINDICATION: ALL

Initial dose level Persons (N=7595) Person-months 100 IU/kg QD 172 82.33150 IU/kg QD 63 16.46300 IU/kg QD 365 239.441-50 IU/kg QW 6 10.7151-200 IU/kg QW 13 21.19450 IU/kg QW 85 603.7600 IU/kg QW 569 1140.5150 IU/kg BIW 29 16.76300 IU/kg BIW 53 32.59600 IU/kg BIW 177 105.41-50 IU/kg TIW 28 51.6151-100 IU/kg TIW 215 649.46101-300 IU/kg TIW 1592 5063.16600 IU/kg TIW 72 112.591,001-5,000 IU QW 211 2680.3110,001-30,000 IU QW 1 13.4740,000 IU QW 2686 18882.9980,000 IU QW 9 50.510,000-20,000 IU Q2W 116 469.0360,000-80,000 IU Q2W 7 26.74120,000 IU Q3W 4 13.34500-5,000 IU TIW 125 230.315,001-15,000 IU TIW 964 3057.18Missing 33 13.93Total 7595 33583.7BIW=2 times a week; QD=once daily; QW=once weekly; Q2W=every 2 weeks; Q3W=every 3 weeks; TIW=3 times a week;NOTE: Forty-nine of the 7,595 patients are missing exposure data and are not included in the calculation of person-months.Chronic Renal Failure – Dialysis Trials: EP86-001 (CEO-C01), EP86-004Chronic Renal Failure – Predialysis Trials: EPO-AUS-14, EPO-CAN-10, EPO-ITA-7, EPOCKD2002, G86-011, H87-054.Oncology Trials: CISPLATIN (I88-036, OEO-U24 and OEO-U25), NON-CHEMOTHERAPY (H87-032, OEO-U20 and OEOU21), NON-CISPLATIN (I88-037, OEO-U22 and OEO-U23), AGO/NOGGO (EPO-GER-8), EP92-002, EPO-CAN-15, EPO-CAN-17, EPO-CAN-20, EPO-CAN-203, EPO-CAN-303, EPO-GBR-4, EPO-GBR-7, EPO-GER-20, EPO-GER-22, EPO-GOG-191, EPO-INT-1 (2574-P-416), EPO-INT-10 (EPO-C111-457), EPO-INT-2 (CC2574-P-467), EPO-INT-3 (2574-P-034), EPO-INT-45, EPO-INT-47, EPO-INT-49, EPO-INT-50, EPO-INT-51 (EPO-CA-484), EPO-INT-76 (EPO-CA-489), EPO-J89-040 (J89-040), EPO-N93-004 (N93-004), EPO-P-169 (2574-P-169), EPO-P-174 (CC2574-P-174), MOEBUS, OBE/EPO-INT-03, PR00-03-006, PR00-27-005, PR98-27-008, PR99-11-034/044, PRI/EPO-NED-17, RTOG/PR99-03-046 (PR99-03-046), EPO-CAN-29, EPO-ANE-3010ABD Trials: CC 2574-P-159, CC 2574-P-165, CC 2574-P-166, H87-017, H87-036, I88-027, I88-058Surgery Trials: EPO-APO2-474, EPO-INT-34 (EPO-AP02-478), CEO-C04, H87-083, J89-001, M92-011, PR97-19-002 (spine)MDS Trials: EPO-ANE-3018 and EPOANE3021



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Table 5:Exposure by Age Group and Gender; All Randomised Controlled Clinical TrialsINDICATION: CHRONIC RENAL FAILURE - DIALYSIS

Men WomenPersons Person-months Persons Person-months

Age Group (N=57) (N=40)<18 years 0 - 0 -18 - 39 years 23 125.3 14 73.9240 - 49 years 9 40.74 9 44.3550 - 59 years 8 41.30 10 49.6460 - 64 years 5 22.74 4 7.4365 - 69 years 5 30.06 1 2.0070 - 74 years 5 8.61 2 7.2975 - 79 years 2 12.02 0 0.0080 - 84 years 0 - 0 ->=85 years 0 - 0 -Missing 0 0.00 0 0.00Chronic Renal Failure – Dialysis Trials: EP86-001 (CEO-C01), EP86-004


INDICATION: CHRONIC RENAL FAILURE - PREDIALYSISMen Women

Persons Person-months Persons Person-monthsAge Group (N=226) (N=238)<18 years 0 0.00 1 4.5718 - 39 years 23 251.6 29 277.740 - 49 years 31 276.2 29 387.150 - 59 years 42 310.7 29 150.660 - 64 years 28 173.7 23 304.765 - 69 years 35 176.5 25 153.970 - 74 years 31 243.4 15 105.075 - 79 years 17 109.7 18 89.8980 - 84 years 6 27.60 21 96.36>=85 years 13 55.82 48 191.1Missing 0 0.00 0 0.00NOTE: One of the 464 patients is missing exposure data and is not included in the calculation of person-months.Chronic Renal Failure – Predialysis Trials: EPO-AUS-14, EPO-CAN-10, EPO-ITA-7, EPOCKD2002, G86-011, H87-054.



69

INDICATION: ONCOLOGYMen Women

Persons Person-months Persons Person-monthsAge Group (N=1504) (N=3819)<18 years 137 561.1 107 581.418 - 39 years 36 122.3 403 268140 - 49 years 135 390.8 852 532350 - 59 years 315 952.0 1170 773460 - 64 years 243 740.1 505 319665 - 69 years 271 818.1 342 187670 - 74 years 216 640.1 280 126575 - 79 years 104 281.8 119 562.580 - 84 years 35 99.02 30 103.7>=85 years 12 19.22 11 23.85Missing 0 0.00 0 0.00NOTE: Five of the 5,323 patients are missing exposure data and are not included in the calculation of person-months.Oncology Trials: CISPLATIN (I88-036, OEO-U24 and OEO-U25), NON-CHEMOTHERAPY (H87-032, OEO-U20 and OEOU21), NON-CISPLATIN (I88-037, OEO-U22 and OEO-U23), AGO/NOGGO (EPO-GER-8), EP92-002, EPO-CAN-15, EPO-CAN-17, EPO-CAN-20, EPO-CAN-203, EPO-CAN-303, EPO-GBR-4, EPO-GBR-7, EPO-GER-20, EPO-GER-22, EPO-GOG-191, EPO-INT-1 (2574-P-416), EPO-INT-10 (EPO-C111-457), EPO-INT-2 (CC2574-P-467), EPO-INT-3 (2574-P-034), EPO-INT-45, EPO-INT-47, EPO-INT-49, EPO-INT-50, EPO-INT-51 (EPO-CA-484), EPO-INT-76 (EPO-CA-489), EPO-J89-040 (J89-040), EPO-N93-004 (N93-004), EPO-P-169 (2574-P-169), EPO-P-174 (CC2574-P-174), MOEBUS, OBE/EPO-INT-03, PR00-03-006, PR00-27-005, PR98-27-008, PR99-11-034/044, PRI/EPO-NED-17, RTOG/PR99-03-046 (PR99-03-046), EPO-ANE-3010, EPO-CAN-29


INDICATION:AUTOLOGOUS BLOOD DONATIONMen Women

Persons Person-months Persons Person-monthsAge Group (N=143) (N=259)<18 years 3 1.77 3 1.8418 - 39 years 24 27.66 28 29.2140 - 49 years 20 21.88 21 19.0250 - 59 years 35 39.29 63 62.2960 - 64 years 27 23.23 43 36.4765 - 69 years 15 11.33 42 29.2770 - 74 years 14 8.97 33 24.5475 - 79 years 3 1.77 17 10.7180 - 84 years 2 1.22 8 4.90>=85 years 0 0.00 1 0.66Missing 0 0.00 0 0.00NOTE: Two women (1 in the 18- to 39-year age group and 1 in the 50- to 59-year age group) are missing exposure data and are not included in the calculation of person-months.ABD Trials: CC 2574-P-159, CC 2574-P-165, CC 2574-P-166, H87-017, H87-036, I88-027, I88-058[TSUB05D.rtf] [JNJ-7472179\Z_RMP\RMP_2015\RE_RMP_2015_EU\tsub05d.sas] 09OCT2015, 14:55


70

INDICATION: SURGERYMen Women

Persons Person-months Persons Person-monthsAge Group (N=368) (N=839)<18 years 0 - 0 -18 - 39 years 24 16.66 47 28.9840 - 49 years 33 16.23 84 56.1550 - 59 years 67 29.90 143 92.9160 - 64 years 63 28.48 109 72.7165 - 69 years 73 37.13 126 80.9970 - 74 years 41 25.66 132 77.8075 - 79 years 41 23.95 116 74.6180 - 84 years 19 11.33 61 36.27>=85 years 6 3.58 21 12.71Missing 1 0.00 0 0.00NOTE: Forty-on of the 1,207 patients are missing exposure data and are not included in the calculation of person-months.Surgery Trials: EPO-APO2-474, EPO-INT-34 (EPO-AP02-478), CEO-C04, H87-083, J89-001, M92-011, PR97-19-002 (spine)


INDICATION: MDS Men Women

Persons Person-months Persons Person-monthsAge Group (N=63) (N=39)<18 years 0 - 0 -18 - 39 years 0 - 0 -40 - 49 years 1 1.64 1 5.4950 - 59 years 3 10.48 1 8.3460 - 64 years 4 24.41 3 22.1465 - 69 years 8 59.47 4 22.7770 - 74 years 15 102.18 12 76.3275 - 79 years 16 103.98 7 53.1680 - 84 years 8 52.01 8 65.12>=85 years 8 42.35 3 27.73Missing 0 0.00 0 0.00MDS Trials: EPO-ANE-3018 and EPOANE3021



71

Table 6: Exposure by Age Group and Gender (Totals); All Randomised Controlled Clinical TrialsINDICATION: ALL

Men WomenPersons Person-months Persons Person-months

Age Group (N=2361) (N=5234)<18 years 140 562.89 111 587.8318 - 39 years 130 543.51 521 3091.0640 - 49 years 229 747.53 996 5835.6050 - 59 years 470 1383.75 1416 8097.7760 - 64 years 370 1012.63 687 3639.5665 - 69 years 407 1132.58 540 2165.2970 - 74 years 322 1028.90 474 1556.2475 - 79 years 183 533.22 277 790.8380 - 84 years 70 191.18 128 306.33>=85 years 39 120.97 84 256.03Missing 1 0.00 0 0.00NOTE: Forty-nine of the 7,595 patients are missing exposure data and are not included in the calculation of person-months.Chronic Renal Failure – Dialysis Trials: EP86-001 (CEO-C01), EP86-004Chronic Renal Failure – Predialysis Trials: EPO-AUS-14, EPO-CAN-10, EPO-ITA-7, EPOCKD2002, G86-011, H87-054.Oncology Trials: CISPLATIN (I88-036, OEO-U24 and OEO-U25), NON-CHEMOTHERAPY (H87-032, OEO-U20 and OEOU21), NON-CISPLATIN (I88-037, OEO-U22 and OEO-U23), AGO/NOGGO (EPO-GER-8), EP92-002, EPO-CAN-15, EPO-CAN-17, EPO-CAN-20, EPO-CAN-203, EPO-CAN-303, EPO-GBR-4, EPO-GBR-7, EPO-GER-20, EPO-GER-22, EPO-GOG-191, EPO-INT-1 (2574-P-416), EPO-INT-10 (EPO-C111-457), EPO-INT-2 (CC2574-P-467), EPO-INT-3 (2574-P-034), EPO-INT-45, EPO-INT-47, EPO-INT-49, EPO-INT-50, EPO-INT-51 (EPO-CA-484), EPO-INT-76 (EPO-CA-489), EPO-J89-040 (J89-040), EPO-N93-004 (N93-004), EPO-P-169 (2574-P-169), EPO-P-174 (CC2574-P-174), MOEBUS, OBE/EPO-INT-03, PR00-03-006, PR00-27-005, PR98-27-008, PR99-11-034/044, PRI/EPO-NED-17, RTOG/PR99-03-046 (PR99-03-046), EPO-CAN-29, EPO-ANE-3010ABD Trials: CC 2574-P-159, CC 2574-P-165, CC 2574-P-166, H87-017, H87-036, I88-027, I88-058Surgery Trials: EPO-APO2-474, EPO-INT-34 (EPO-AP02-478), CEO-C04, H87-083, J89-001, M92-011, PR97-19-002 (spine)MDS Trials: EPO-ANE-3018 and EPOANE3021



72

Table 7:Exposure by Ethnic and Racial Origin; All Randomised Controlled Clinical TrialsINDICATION: CHRONIC RENAL FAILURE - DIALYSIS

Race Persons (N=97) Person-months White 86 412.48Black or African American 1 6.08Asian 3 12.29American Indian or Alaska Native 1 6.01Hispanic or Latino 0 0.00Other a 6 28.52Missing 0 0.00Total 97 465.38a Other races include MISSING (6).Chronic Renal Failure – Dialysis Trials: EP86-001 (CEO-C01), EP86-004


INDICATION: CHRONIC RENAL FAILURE - PREDIALYSISRace Persons (N=464) Person-months White 382 2966.67Black or African American 48 147.75Asian 12 126.36American Indian or Alaska Native 1 5.03Hispanic or Latino 6 25.03Other a 15 115.12Missing 0 0.00Total 464 3385.95a Other races include ABORIGINAL (1), COOK ISLAND (2),EAST-INDIAN (2), MAORI(3), NATIVE HAWAIIAN OR

OTHER PACIFIC ISLANDER (1), RUSSIAN (1), SAMOAN (1) and MISSING (4).NOTE: One of the 464 patients is missing exposure data and is not included in the calculation of person-months.Chronic Renal Failure – Predialysis Trials: EPO-AUS-14, EPO-CAN-10, EPO-ITA-7, EPOCKD2002, G86-011, H87-054.


INDICATION: ONCOLOGYRace Persons (N=5323) Person-months White 3270 17908.40Black or African American 143 421.29Asian 366 4397.96American Indian or Alaska Native 3 6.37Hispanic or Latino 29 100.47Other a 52 487.36Missing 1460 4650.84Total 5323 27972.70a Other races include AFGHAN(1), ANTILLEAN(2), ARAB(1), ASIAN-FILIPINO(2), CARIBBEAN (1), COLOURED(2), EAST-INDIAN(3), EGYPTIAN(1), FIJIAN(1), FIRST NATIONS (NATIVE)(1), GUATEMALAN(1), GYPSY(2), HALF-CASTE(3), HISPANIC(12), INDIAN(1), MESTIZA(1), MIXED RACE(3), MIXED- ASIAN/AFRICAN(1), MOTHER-ASIAN/FATHER CAUCASIAN(1), NATIVE HAWAIIAN(1), PHILIPINO(1), PORTUGESE(1), SURINAM(1), TRINIDADIAN(1) and MISSING (7).NOTE: Five of the 5,323 patients are missing exposure data and are not included in the calculation of person-months.Oncology Trials: CISPLATIN (I88-036, OEO-U24 and OEO-U25), NON-CHEMOTHERAPY (H87-032, OEO-U20 and OEOU21), NON-CISPLATIN (I88-037, OEO-U22 and OEO-U23), AGO/NOGGO (EPO-GER-8), EP92-002,EPO-CAN-15, EPO-CAN-17, EPO-CAN-20, EPO-CAN-203, EPO-CAN-303, EPO-GBR-4, EPO-GBR-7, EPO-GER-20, EPO-GER-22, EPO-GOG-191, EPO-INT-1 (2574-P-416), EPO-INT-10 (EPO-C111-457), EPO-INT-2 (CC2574-P-467), EPO-INT-3 (2574-P-034), EPO-INT-45, EPO-INT-47, EPO-INT-49, EPO-INT-50, EPO-INT-51 (EPO-CA-484), EPO_INT-76 (EPO-CA-489), EPO-J89-040 (J89-040), EPO-N93-004 (N93-004), EPO-P-169 (2574-P-169), EPO-P-174 (CC2574-P-174), MOEBUS, OBE/EPO-INT-03, PR00-03-006, PR00-27-005, PR98-27-008, PR99-11-034/044, PRI/EPO-NED-17, RTOG/PR99-03-046 (PR99-03-046), EPO-ANE-3010, EPO-CAN-29



73

INDICATION: AUTOLOGOUS BLOOD DONATIONRace Persons (N=402) Person-months White 372 338.07Black or African American 24 14.29Asian 0 0.00American Indian or Alaska Native 0 0.00Hispanic or Latino 0 0.00Other a 6 3.68Missing 0 0.00Total 402 356.04a Other races include INDIAN (1) and MISSING (5).NOTE: Two women (1 in the 18- to 39-year age group and 1 in the 50- to 59-year age group) are missing exposure data and are not included in the calculation of person-months.ABD Trials: CC 2574-P-159, CC 2574-P-165, CC 2574-P-166, H87-017, H87-036, I88-027, I88-058


INDICATION:SURGERYRace Persons (N=1207) Person-months White 1042 631.23Black or African American 137 80.69Asian 5 1.91American Indian or Alaska Native 0 0.00Hispanic or Latino 15 9.30Other a 8 2.92Missing 0 0.00Total 1207 726.05a Other races include CAPE VERDIAN (1) and MISSING (7).NOTE: Forty-one of the 1,207 patients are missing exposure data and are not included in the calculation of person-months.Surgery Trials: EPO-APO2-474, EPO-INT-34 (EPO-AP02-478), CEO-C04, H87-083, J89-001, M92-011, PR97-19-002 (spine)


INDICATION: MDSRace Persons (N=102) Person-months White 17 73.89Black or African American 0 0.00Asian 0 0.00American Indian or Alaska Native 0 0.00Hispanic or Latino 0 0.00Other 0 0.00Missing 85 603.70Total 102 677.59MDS Trials: EPO-ANE-3018 and EPOANE3021



74

Table 8:Exposure by Ethnic and Racial Origin and (Totals); All Randomised Controlled Clinical TrialsINDICATION:ALL

Race Persons (N=7595) Person-months White 5169 22330.74Black or African American 353 670.09Asian 386 4538.51American Indian or Alaska Native 5 17.41Hispanic or Latino 50 134.80Other 87 637.60Missing 1545 5254.54Total 7595 33583.70NOTE: Forty-nine of the 7,595 patients are missing exposure data and are not included in the calculation of person-months.Chronic Renal Failure – Dialysis Trials: EP86-001 (CEO-C01), EP86-004Chronic Renal Failure – Predialysis Trials: EPO-AUS-14, EPO-CAN-10, EPO-ITA-7, EPOCKD2002, G86-011, H87-054.Oncology Trials: CISPLATIN (I88-036, OEO-U24 and OEO-U25), NON-CHEMOTHERAPY (H87-032, OEO-U20, and OEOU21), NON-CISPLATIN (I88-037, OEO-U22 and OEO-U23), AGO/NOGGO (EPO-GER-8), EP92-002, EPO-CAN-15, EPO-CAN-17, EPO-CAN-20, EPO-CAN-203, EPO-CAN-303, EPO-GBR-4, EPO-GBR-7, EPO-GER-20, EPO-GER-22, EPO-GOG-191, EPO-INT-1 (2574-P-416), EPO-INT-10 (EPO-C111-457), EPO-INT-2 (CC2574-P-467), EPO-INT-3 (2574-P-034), EPO-INT-45, EPO-INT-47, EPO-INT-49, EPO-INT-50, EPO-INT-51 (EPO-CA-484), EPO-INT-76 (EPO-CA-489), EPO-J89-040 (J89-040), EPO-N93-004 (N93-004), EPO-P-169 (2574-P-169), EPO-P-174 (CC2574-P-174), MOEBUS, OBE/EPO-INT-03, PR00-03-006, PR00-27-005, PR98-27-008, PR99-11-034/044, PRI/EPO-NED-17, RTOG/PR99-03-046 (PR99-03-046), EPO-CAN-29, EPO-ANE-3010ABD Trials: CC 2574-P-159, CC 2574-P-165, CC 2574-P-166, H87-017, H87-036, I88-027, I88-058Surgery Trials: EPO-APO2-474, EPO-INT-34 (EPO-AP02-478), CEO-C04, H87-083, J89-001, M92-011, PR97-19-002 (spine)MDS Trials: EPO-ANE-3018 and EPOANE3021



75

Table 9:Exposure by Special Population; All Randomised Controlled Clinical TrialsINDICATION: CHRONIC RENAL FAILURE - DIALYSIS

Population Category at Baseline Persons Person-months Total (N=97)Hepatic Impairment (n=97)ALT

<=ULN (normal) 76 361.76>ULN to <=2.5 x ULN 12 57.33>2.5 to <=5.0 x ULN 3 18.04>5.0 to <=20.0 x ULN 1 6.01>20.0 x ULN 0 0.0Missing 5

AST<=ULN (normal) 88 414.16>ULN to <=2.5 x ULN 6 33.12>2.5 to <=5.0 x ULN 2 12.09>5.0 to <=20.0 x ULN 0 0.0>20.0 x ULN 0 0.0Missing 1

Bilirubin<=ULN (normal) 96 459.37>ULN to <=1.5 x ULN 0 0.0>1.5 to <=3.0 x ULN 0 0.0>3.0 to <=10.0 x ULN 0 0.0>10.0 x ULN 0 0.0Missing 1

Alkaline phosphatase<=ULN (normal) 72 332.85>ULN to <=2.5 x ULN 21 108.85>2.5 to <=5.0 x ULN 3 17.61>5.0 to <=20.0 x ULN 1 6.08>20.0 x ULN 0 0.0Missing 0

ALT=alanine aminotransferase; AST=aspartate aminotransferase; N/n=number; ULN=upper limit of normal; x=timesOf the 97 patients in the Chronic Renal Failure – Adult Haemodialysis dataset, 97 patients had at least one non-missing hepatic ALT, AST, bilirubin, or alkaline phosphatase measurement. For each parameter measured, some of the 97 patients did not have data available and are counted as missing.Chronic Renal Failure – Dialysis Trials: EP86-001 (CEO-C01), EP86-004



76

INDICATION: CHRONIC RENAL FAILURE - PREDIALYSISPopulation Category at Baseline Persons Person-months Total (N=464)Hepatic Impairment (n=395)ALT





ALT=alanine aminotransferase; AST=aspartate aminotransferase; N/n=number; ULN=upper limit of normal; x=timesPerson-months may be underestimated due to missing exposure data.Of 464 patients in the Chronic Renal Failure – Adult Predialysis dataset, 395 patients had at least one non-missing hepatic ALT, AST, bilirubin, or alkaline phosphatase measurement. For each parameter measured, some of the 395 patients did not have data available and are counted as missing.Chronic Renal Failure – Predialysis Trials: EPO-AUS-14, EPO-CAN-10, EPO-ITA-7, EPOCKD2002, G86-011, H87-054.



77

INDICATION: ONCOLOGYPopulation Category at Baseline Persons Person-months

Total (N=5323)Hepatic Impairmenta (n=3130)ALT





Renal impairment (n=3372)Mild (CrCl>50 to <80 mL/min) 1342 8477.14Moderate (CrCl>30 to <=50 mL/min) 339 1791.84Severe (CrCl<=30 mL/min) 43 139.14Missing or Otherb 1648

ALT=alanine aminotransferase; AST=aspartate aminotransferase; CrCl=creatinine clearance; min=minute; N/n=number; x=times; ULN-upper limit of normalPerson-months may be underestimated due to missing exposure data.a Of the 5,323 patients in the oncology dataset, 3,130 patients had data measuring hepatic impairment. For each parameter measured, some patients did not have data available and are counted as missing.b Of the 3,372 patients with CrCl data, only 1,724 patients were categorized as mild, moderate, or severe with respect to renal impairment. The remaining 1,648 patients were normal or missing baseline CrCl.Oncology Studies: CISPLATIN (I88-036, OEO-U24 and OEO-U25), NON-CHEMOTHERAPY (H87-032, OEO-U20, and OEOU21), NON-CISPLATIN (I88-037, OEO-U22, and OEO-U23), AGO/NOGGO (EPO-GER-8), EP92-002, EPO-CAN-15, EPO-CAN-17, EPO-CAN-20, EPO-CAN-203, EPO-CAN-303, EPO-GBR-4, EPO-GBR-7, EPO-GER-20, EPO-GER-22, EPO-GOG-191, EPO-INT-1 (2574-P-416), EPO-INT-10 (EPO-C111-457), EPO-INT-2 (CC2574-P-467), EPO-INT-3 (2574-P-034), EPO-INT-45, EPO-INT-47, EPO-INT-49, EPO-INT-50, EPO-INT-51 (EPO-CA-484), EPO-INT-76 (EPO-CA-489), EPO-J89-040 (J89-040), EPO-N93-004 (N93-004), EPO-P-169 (2574-P-169), EPO-P-174 (CC2574-P-174), MOEBUS, OBE/EPO-INT-03, PR00-03-006, PR00-27-005, PR98-27-008, PR99-11-034/044, PRI/EPO-NED-17, RTOG/PR99-03-046 (PR99-03-046), EPO-ANE-3010, EPO-CAN-29

[TSUB09C.rtf] [JNJ-7472179\Z_RMP\RMP_2015\RE_RMP_2015_EU\tsub09c.sas] 18JAN2016, 17:34


78

INDICATION:AUTOLOGOUS BLOOD DONATIONPopulation Category at Baseline Persons Person-months Total (N=402)Hepatic Impairmenta (n=398)ALT






ABD=autologous blood donation; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CrCl=creatinine clearance; N/n=number; ULN=upper limit of normal; x=timesPerson-months may be underestimated due to missing exposure data.a Of the 402 patients in the ABD dataset, 398 patients had data measuring hepatic impairment. For each parameter measured, some patients did not have data available and are counted as missing.b Of the 390 patients with CrCl data, only 186 patients were categorized as mild, moderate, or severe with respect to renal impairment. The remaining 204 patients were normal or missing baseline CrCl.ABD Trials: CC 2574-P-159, CC 2574-P-165, CC 2574-P-166, H87-017, H87-036, I88-027, I88-058



79

INDICATION:SURGERYPopulation Category at Baseline Persons Person-months Total (N=1207)Hepatic Impairmenta (n=830)ALT




Alkaline phosphatase



ALT=alanine aminotransferase; AST=aspartate aminotransferase; CrCl=creatinine clearance; N/n=number; ULN=upper limit of normal; x=timesPerson-months may be underestimated due to missing exposure data.a Of the 1,207 patients in the Surgery dataset, 830 patients had data measuring hepatic impairment. For each parameter measured, some patients did not have data available and are counted as missing.b Of the 1,158 patients with CrCl data, only 625 patients were categorized as mild, moderate, or severe with respect to renal impairment. The remaining 533 patients were normal or missing baseline CrCl.Surgery Trials: EPO-APO2-474, EPO-INT-34 (EPO-AP02-478), CEO-C04, H87-083, J89-001, M92-011, PR97-19-002 (spine)



80

INDICATION: MDSPopulation Category at Baseline Persons Person-months Total (N=102)Hepatic Impairment (n=99)ALT





ALT=alanine aminotransferase; AST=aspartate aminotransferase; MDS=myelodysplastic syndrome; N/n=number; ULN=upper limit of normal; x=timesOf the 102 patients in the MDS dataset, 99 patients had data at least one non-missing hepatic ALT, AST, bilirubin, or alkaline phosphatase measurement. For each parameter measured, some of the 99 patients did not have data available and are counted as missing.MDS Trials: EPO-ANE-3018 and EPOANE3021



81

Table 10: Exposure by Special Population (Totals); All Randomised Controlled Clinical Trials

INDICATION:ALLPopulation Category at Baseline Persons Person-months







ALT=alanine aminotransferase; AST=aspartate aminotransferase; CrCl=creatinine clearance; N/n=number; ULN=upper limit of normal; x=times;Person-months may be underestimated due to missing exposure data.a Of the 7,595 patients, 4,949 patients had data measuring hepatic impairment. For each parameter measured, some patientsdid not have data available and are counted as missing.For Renal Impairment, only trials associated with the oncology, ABD, and surgery indications are includedb Of the 4,920 patients with CrCl data, only 2,535 patients were categorized as mild, moderate, or severe with respect to renal impairment. The remaining 2,385 patients were normal or missing baseline CrCl.Chronic Renal Failure – Dialysis Studies: EP86-001 (CEO-C01), EP86-004Chronic Renal Failure – Predialysis Studies: EPO-AUS-14, EPO-CAN-10, EPO-ITA-7, EPOCKD2002, G86-011, H87-054.Oncology Studies: CISPLATIN (I88-036, OEO-U24, and OEO-U25), NON-CHEMOTHERAPY (H87-032, OEO-U20, and OEOU21), NON-CISPLATIN (I88-037, OEO-U22, and OEO-U23), AGO/NOGGO (EPO-GER-8), EP92-002, EPO-CAN-15, EPO-CAN-17, EPO-CAN-20, EPO-CAN-203, EPO-CAN-303, EPO-GBR-4, EPO-GBR-7, EPO-GER-20, EPO-GER-22, EPO-GOG-191, EPO-INT-1 (2574-P-416), EPO-INT-10 (EPO-C111-457), EPO-INT-2 (CC2574-P-467), EPO-INT-3 (2574-P-034), EPO-INT-45, EPO-INT-47, EPO-INT-49, EPO-INT-50, EPO-INT-51 (EPO-CA-484), EPO-INT-76 (EPO-CA-489), EPO-J89-040 (J89-040), EPO-N93-004 (N93-004), EPO-P-169 (2574-P-169), EPO-P-174 (CC2574-P-174), MOEBUS, OBE/EPO-INT-03, PR00-03-006, PR00-27-005, PR98-27-008, PR99-11-034/044, PRI/EPO-NED-17, RTOG/PR99-03-046 (PR99-03-046), EPO-CAN-29, EPO-ANE-3010ABD Studies: CC 2574-P-159, CC 2574-P-165, CC 2574-P-166, H87-017, H87-036, I88-027, I88-058Surgery Studies: EPO-APO2-474, EPO-INT-34 (EPO-AP02-478), CEO-C04, H87-083, J89-001, M92-011, PR97-19-002 (spine)MDS Studies: EPO-ANE-3018 and EPOANE3021

[TSUB010.rtf] [JNJ-7472179\Z_RMP\RMP_2015\RE_RMP_2015_EU\tsub010.sas] 19JAN2016, 10:50


82

Exposure in All Clinical Trials Including Open Extensions

Exposure to EPREX in all clinical trials is summarised in Tables 11 through 20 for all patients

by duration, dose, age and sex, ethnic and racial origin, baseline renal status, and baseline hepatic

status.

In the all clinical trials population, the 15,339 EPREX-treated patients received

94,676.17 person-months exposure to EPREX; this represents an increase of

61,092.47 person-months exposure to EPREX compared with the randomised controlled trials

population.

In the all clinical trials population of 15,339 EPREX-treated patients:

There were 94,676.17 person-months exposure to EPREX (Tables 11 and 12)

A total of 5,844 (38%) patients were men and 9,393 (62%) patients were women (Tables 15 and 16)

A total of 6,385 (42%) patients were 65 years of age or older, while 2,560 (17%) patients were 75 years of age or older (Tables 15 and 16)

A majority of patients (10,515 [69%]) were White, while 1,926 (13%) patients were Black,and 1,353 (9%) patients were Asian, Hispanic or Latino, American Indian or Alaska Native, or Other (Tables 17 and 18); data on ethnic and racial origin were missing for 1,545 (10%) patients

At total of 5,534 (72%) of the 7,683 patients in the cancer, ABD, surgery, or MDS trials captured in the laboratory database had mild (CRCL >50 to <80 mL/min; n= 2,178), moderate (CRCL >30 to 50 mL/min; n=658), or severe (CRCL 30 mL/min; n=73) renal impairment at baseline (Tables 19 and 20); CRCL data at baseline were missing or noted as normal in the database for 2,625 patients (Note: only trials associated with the cancer, ABD, surgery, and MDS indications were included in this evaluation because CRF was evaluated as a separate indication by itself.)


83

Table 11: Exposure by Duration; All Clinical Trials Including Open ExtensionINDICATION: CHRONIC RENAL FAILURE - DIALYSIS

Duration of Exposure Persons (N=2046) Person-months Cumulative up to 1 month 81 44.32Cumulative up to 3 months 387 655.44Cumulative up to 6 months 897 2900.53Cumulative up to 9 months 1281 5502.09Cumulative up to 12 months 1409 6827.99Cumulative up to 18 months 1650 10552.38Cumulative up to 24 months 2013 18506.22Missing 33 .Chronic Renal Failure – Dialysis Trials: EP86-001 (CEO-C01), EP86-004, EPO-CAN-1, EPO-CAN-13, EPO-INT-37, EPO-INT-68, EPO-INT-77, EPO-ITA-2, ZEO-107 (CCP107P108), ZEO-121 (CC2574P121), ZEO-S01 (CCP102P103)


INDICATION: CHRONIC RENAL FAILURE - PREDIALYSISDuration of Exposure Persons (N=5610) Person-months Cumulative up to 1 month 328 159.77Cumulative up to 3 months 1121 1778.89Cumulative up to 6 months 3236 9652.86Cumulative up to 9 months 3815 14204.81Cumulative up to 12 months 4294 19169.71Cumulative up to 18 months 4924 28460.19Cumulative up to 24 months 5380 38000.39Cumulative up to 36 months 5602 44429.5Cumulative up to 48 months 5608 44689.08Missing 2 .Chronic Renal Failure – Predialysis Trials: CHOIR (PR00-06014), EPOCKD2001, EPOCKD2002, EPO-AKD-3001, EPO-AKD-3002, EPO-AUS-14, EPO-CAN-10, EPO-INT-14, EPO-ITA-7, G86-011, G86-053, G86-125, H87-054, H87-055, N93-063, POWER (PR00-06009), PROMPT (PR01-06021), Q2W INITIATION (PR03-06001), EPO-NED-15


INDICATION: ONCOLOGYDuration of Exposure Persons (N=5827) Person-months Cumulative up to 1 month 651 219.56Cumulative up to 3 months 2448 4166.18Cumulative up to 6 months 4703 13750.93Cumulative up to 9 months 5037 16114.69Cumulative up to 12 months 5261 18569.69Cumulative up to 18 months 5586 22901.06Cumulative up to 24 months 5693 25102.46Cumulative up to 36 months 5774 27406Cumulative up to 48 months 5810 28890.58Cumulative up to 60 months 5816 29224.87Cumulative up to 72 months 5821 29559.2Cumulative up to 84 months 5822 29634.46Missing 5 .Oncology Trials: CISPLATIN (I88-036, OEO-U24, and OEO-U25), NON-CHEMOTHERAPY (H87-032, OEO-U20, and OEOU21), NON-CISPLATIN (I88-037, OEO-U22, and OEO-U23), AGO/NOGGO (EPO-GER-8), EP92-002, EPO-ANE-4008, EPO-CAN-15, EPO-CAN-17, EPO-CAN-20, EPO-CAN-203, EPO-CAN-303, EPO-GBR-4, EPO-GBR-7, EPO-GER-20, EPO-GER-22, EPO-GOG-191, EPO-INT-1 (2574-P-416), EPO-INT-10 (EPO-C111-457), EPO-INT-2 (CC2574-P-467), EPO-INT-3 (2574-P-034), EPO-INT-45, EPO-INT-47, EPO-INT-49, EPO-INT-50, EPO-INT-51 (EPO-CA-484), EPO-INT-76 (EPO-CA-489), EPO-J89-040 (J89-040), EPO-N93-004 (N93-004), EPO-P-169 (2574-P-169), EPO-P-174 (CC2574-P-174), MOEBUS, OBE/EPO-INT-03, PR00-03-006, PR00-27-005, PR98-27-008, PR99-11-034/044, PRI/EPO-NED-17, RTOG/PR99-03-046 (PR99-03-046), EPO-ANE-3010, EPO-CAN-29



84

INDICATION:AUTOLOGOUS BLOOD DONATIONDuration of Exposure Persons (N=402) Person-months Cumulative up to 1 month 316 199.49Cumulative up to 3 months 389 311.36Cumulative up to 6 months 399 349.6Cumulative up to 9 months 400 356.04Cumulative up to 12 months 400 356.04Cumulative up to 18 months 400 356.04Cumulative up to 24 months 400 356.04Missing 2 .ABD Trials: CC 2574-P-159, CC 2574-P-165, CC 2574-P-166, H87-017, H87-036, I88-027, I88-058


INDICATION: SURGERYDuration of Exposure Persons (N=1352) Person-months Cumulative up to 1 month 1251 725.06Cumulative up to 3 months 1309 805.49Cumulative up to 6 months 1311 812.78Cumulative up to 9 months 1311 812.78Cumulative up to 12 months 1311 812.78Cumulative up to 18 months 1311 812.78Cumulative up to 24 months 1311 812.78Missing 41 .Surgery Trials: EPO-APO2-474, EPO-INT-34 (EPO-AP02-478), CEO-C04, H87-083, J89-001, M92-011, N93-057, PR97-19-002 (spine)


INDICATION: MDSDuration of Exposure Persons (N=102) Person-months Cumulative up to 1 month 6 2.37Cumulative up to 3 months 18 27.53Cumulative up to 6 months 60 247.39Cumulative up to 9 months 67 297.3Cumulative up to 12 months 102 677.59Cumulative up to 18 months 102 677.59Cumulative up to 24 months 102 677.59MDS Trials: EPO-ANE-3018 and EPOANE3021



85

Table 12: Exposure by Duration (Totals); All Clinical Trials Including Open ExtensionINDICATION: ALL

Duration of Exposure Persons (N=15339) Person-months Cumulative up to 1 month 2633 1350.57Cumulative up to 3 months 5672 7744.89Cumulative up to 6 months 10606 27714.1Cumulative up to 9 months 11911 37287.72Cumulative up to 12 months 12777 46413.8Cumulative up to 18 months 13973 63760.03Cumulative up to 24 months 14899 83455.47Cumulative up to 36 months 15202 92188.12Cumulative up to 48 months 15244 93932.29Cumulative up to 60 months 15250 94266.58Cumulative up to 72 months 15255 94600.9Cumulative up to 84 months 15256 94676.17Missing 83 .Chronic Renal Failure – Dialysis Trials: EP86-001 (CEO-C01), EP86-004, EPO-CAN-1, EPO-CAN-13, EPO-INT-37, EPO-INT-68, EPO-INT-77, EPO-ITA-2, ZEO-107 (CCP107P108), ZEO-121 (CC2574P121), ZEO-S01 (CCP102P103)Chronic Renal Failure – Predialysis Trials: CHOIR (PR00-06014), EPOCKD2001, EPOCKD2002, EPO-AKD-3001, EPO-AKD-3002, EPO-AUS-14, EPO-CAN-10, EPO-INT-14, EPO-ITA-7, G86-011, G86-053, G86-125, H87-054, H87-055, N93-063, POWER (PR00-06009), PROMPT (PR01-06021), Q2W INITIATION (PR03-06001), EPO-NED-15.Oncology Trials: CISPLATIN (I88-036, OEO-U24 and OEO-U25), NON-CHEMOTHERAPY (H87-032, OEO-U20 and OEOU21), NON-CISPLATIN (I88-037, OEO-U22 and OEO-U23), AGO/NOGGO (EPO-GER-8), EP92-002, EPO-ANE-4008, EPO-CAN-15, EPO-CAN-17, EPO-CAN-20, EPO-CAN-203, EPO-CAN-303, EPO-GBR-4, EPO-GBR-7, EPO-GER-20, EPO-GER-22, EPO-GOG-191, EPO-INT-1 (2574-P-416), EPO-INT-10 (EPO-C111-457), EPO-INT-2 (CC2574-P-467),EPO-INT-3 (2574-P-034), EPO-INT-45, EPO-INT-47, EPO-INT-49, EPO-INT-50, EPO-INT-51 (EPO-CA-484), EPO-INT-76 (EPO-CA-489), EPO-J89-040 (J89-040), EPO-N93-004 (N93-004), EPO-P-169 (2574-P-169), EPO-P-174 (CC2574-P-174), MOEBUS, OBE/EPO-INT-03, PR00-03-006, PR00-27-005, PR98-27-008, PR99-11-034/044, PRI/EPO-NED-17, RTOG/PR99-03-046 (PR99-03-046), EPO-CAN-29, EPO-ANE-3010ABD Trials: CC 2574-P-159, CC 2574-P-165, CC 2574-P-166, H87-017, H87-036, I88-027, I88-058Surgery Trials: EPO-APO2-474, EPO-INT-34 (EPO-AP02-478), CEO-C04, H87-083, J89-001, M92-011, N93-057, PR97-19-002 (spine)MDS Trials: EPO-ANE-3018 and EPOANE3021[TSUB012.rtf] [JNJ-7472179\Z_RMP\RMP_2015\RE_RMP_2015_EU\tsub012.sas] 09OCT2015, 14:59

Table 13: Exposure by Dose; All Clinical Trials Including Open ExtensionINDICATION: CHRONIC RENAL FAILURE - DIALYSIS

Initial dose level Persons (N=2046) Person-months 10-50 IU/kg QW 170 448.3951-200 IU/kg QW 13 21.191-50 IU/kg TIW 50 264.0551-100 IU/kg TIW 215 776.05500-5,000 IU BIW 114 601.45,001-10,000 IU BIW 94 372.37500-1,000 IU QW 20 272.821,001-5,000 IU QW 483 6508.815,001-10,000 IU QW 465 6185.5910,001-30,000 IU QW 151 1820.16500-5,000 IU TIW 93 527.875,001-15,000 IU TIW 131 527.01Missing 47 180.5Total 2046 18506.22BIW=2 times a week; N=number; QW=once weekly; TIW=3 times a weekNOTE: Thirty-three of the 2,046 patients are missing exposure data and are not included in the calculation of person-months.Chronic Renal Failure – Dialysis Trials: EP86-001 (CEO-C01), EP86-004, EPO-CAN-1, EPO-CAN-13, EPO-INT-37, EPO-INT-68, EPO-INT-77, EPO-ITA-2, ZEO-107 (CCP107P108), ZEO-121 (CC2574P121), ZEO-S01 (CCP102P103)


INDICATION: CHRONIC RENAL FAILURE - PREDIALYSISInitial dose level Persons (N=5610) Person-months 1-50 IU/kg QW 156 1532.9151-200 IU/kg QW 99 1056.2


86

1-50 IU/kg TIW 99 624.6651-100 IU/kg TIW 172 1365.45101-300 IU/kg TIW 105 921.79500-1,000 IU QW 7 44.811,001-5,000 IU QW 276 3196.455,001-10,000 IU QW 3298 28287.1510,001-20,000 IU QW 9 71.7510,000-20,000 IU Q2W 612 3335.3320,001-40,000 IU Q2W 9 45.3430,000 IU Q3W 131 389.1320,000-40,000 IU Q4W 461 2293.0960,000-80,000 IU Q4W 22 150.14500-5,000 IU TIW 117 1068.945,001-10,000 IU TIW 6 59.43Missing 31 246.51Total 5610 44689.08N=number; QW=once weekly; Q2W=every 2 weeks; Q4W=every 4 weeks; TIW=3 times a weekNOTE: Two of the 5,610 patients are missing exposure data and are not included in the calculation of person-months.Chronic Renal Failure – Predialysis Trials: CHOIR (PR00-06014), EPOCKD2001, EPOCKD2002, EPO-AKD-3001, EPO-AKD-3002, EPO-AUS-14, EPO-CAN-10, EPO-INT-14, EPO-ITA-7, G86-011, G86-053, G86-125, H87-054, H87-055, N93-063, POWER (PR00-06009), PROMPT (PR01-06021), Q2W INITIATION (PR03-06001), EPO-NED-15


INDICATION: ONCOLOGYInitial dose level Persons (N=5827) Person-months 450 IU/kg QW 242 823.49600 IU/kg QW 228 912.36100 IU/kg TIW 65 98.76150 IU/kg TIW 1629 5280.39300 IU/kg TIW 124 490.1840,000 IU QW 2437 18699.9360,000-80,000 IU Q2W 7 26.74120,000 IU Q3W 4 13.344,000-5,000 IU TIW 125 230.3110,000 IU TIW 964 3057.18Missing 2 1.77Total 5827 29634.46N=number; QW=once weekly; Q2W=once every 2 weeks; Q3W=once every 3 weeks; TIW=3 times a weekNOTE: Five of the 5,827 patients are missing exposure data and are not included in the calculation of person-months.Oncology Trials: CISPLATIN (I88-036, OEO-U24 and OEO-U25), NON-CHEMOTHERAPY (H87-032, OEO-U20 and OEOU21), NON-CISPLATIN (I88-037, OEO-U22 and OEO-U23), AGO/NOGGO (EPO-GER-8), EP92-002, EPO-ANE-4008, EPO-CAN-15, EPO-CAN-17, EPO-CAN-20, EPO-CAN-203, EPO-CAN-303, EPO-GBR-4, EPO-GBR-7, EPO-GER-20, EPO-GER-22, EPO-GOG-191, EPO-INT-1 (2574-P-416), EPO-INT-10 (EPO-C111-457), EPO-INT-2 (CC2574-P-467), EPO-INT-3 (2574-P-034), EPO-INT-45, EPO-INT-47, EPO-INT-49, EPO-INT-50, EPO-INT-51 (EPO-CA-484), EPO-INT-76 (EPO-CA-489), EPO-J89-040 (J89-040), EPO-N93-004 (N93-004), EPO-P-169 (2574-P-169), EPO-P-174 (CC2574-P-174), MOEBUS, OBE/EPO-INT-03, PR00-03-006, PR00-27-005, PR98-27-008, PR99-11-034/044, PRI/EPO-NED-17, RTOG/PR99-03-046 (PR99-03-046), EPO-ANE-3010, EPO-CAN-29



87

INDICATION:AUTOLOGOUS BLOOD DONATIONInitial dose level Persons (N=402) Person-months 150 IU/kg BIW 29 16.76300 IU/kg BIW 53 32.59600 IU/kg BIW 177 105.4300 IU/kg TIW 71 88.71600 IU/kg TIW 72 112.59Total 402 356.04BIW=2 times a week; N-number; TIW=3 times a weekNOTE: Two women (1 in the 18- to 39-year age group and 1 in the 50-to 59-year age group) are missing exposure data and are not included in the calculation of person-months.ABD Trials: CC 2574-P-159, CC 2574-P-165, CC 2574-P-166, H87-017, H87-036, I88-027, I88-058


INDICATION:SURGERYInitial dose level Persons (N=1352) Person-months 100 IU/kg QD 172 82.33150 IU/kg QD 63 16.46300 IU/kg QD 437 274.89600 IU/kg QW 414 279.4340,000 IU QW 241 159.67Missing 25 .Total 1352 812.78N=number; QD=once daily; QW=once weeklyNOTE: Forty-one of the 1,352 patients are missing exposure data and are not included in the calculation of person-months.Surgery Trials: EPO-APO2-474, EPO-INT-34 (EPO-AP02-478), CEO-C04, H87-083, J89-001, M92-011, N93-057, PR97-19-002 (spine)


INDICATION: MDSInitial dose level Persons(N=102) Person-months 450 IU/kg QW 85 603.740,000 IU QW 8 23.3980,000 IU QW 9 50.5Total 102 677.59MDS=myelodysplastic syndrome; N=number; QW=once weeklyMDS Trials: EPO-ANE-3018 and EPOANE3021



88

Table 14: Exposure by Dose (Totals); All Clinical Trials Including Open Extension

INDICATION:ALLInitial dose level Persons (N=15339) Person-months

100 IU/kg QD 172 82.33150 IU/kg QD 63 16.46300 IU/kg QD 437 274.891-50 IU/kg QW 326 1981.3151-200 IU/kg QW 112 1077.39450 IU/kg QW 327 1427.19600 IU/kg QW 642 1191.79150 IU/kg BIW 29 16.76300 IU/kg BIW 53 32.59600 IU/kg BIW 177 105.41-50 IU/kg TIW 149 888.7151-100 IU/kg TIW 452 2240.26101-300 IU/kg TIW 1929 6781.08600 IU/kg TIW 72 112.59500-5,000 IU BIW 114 601.45,001-10,000 IU BIW 94 372.37500-1,000 IU QW 27 317.631,001-5,000 IU QW 759 9705.265,001-10,000 IU QW 3763 34472.7410,001-30,000 IU QW 160 1891.9140,000 IU QW 2686 18882.9980,000 IU QW 9 50.510,000-20,000 IU Q2W 612 3335.3320,001-40,000 IU Q2W 9 45.3460,000-80,000 IU Q2W 7 26.7430,000 IU Q3W 131 389.13120,000 IU Q3W 4 13.3420,000-40,000 IU Q4W 461 2293.0960,000-80,000 IU Q4W 22 150.14500-5,000 IU TIW 335 1827.125,001-15,000 IU TIW 1101 3643.63Missing 105 428.78Total 15339 94676.17

ABD=autologous blood donation; BIW=2 times a week; MDS=myelodysplastic syndrome; N=number; QD=once daily; QW=once weekly; Q2W=once every 2 weeks; Q3W=once every 3 weeks; Q4W=once every 4 weeks; TIW=3 times a weekNOTE: Eighty-three of the 15,339 patients are missing exposure data and are not included in the calculation of person-monthsChronic Renal Failure – Dialysis trials: EP86-001 (CEO-C01), EP86-004, EPO-CAN-1, EPO-CAN-13, EPO-INT-37, EPO-INT-68, EPO-INT-77, EPO-ITA-2, ZEO-107 (CCP107P108), ZEO-121 (CC2574P121), ZEO-S01 (CCP102P103)Chronic Renal Failure – Predialysis trials: CHOIR (PR00-06014), EPOCKD2001, EPOCKD2002, EPO-AKD-3001, EPO-AKD-3002, EPO-AUS-14, EPO-CAN-10, EPO-INT-14, EPO-ITA-7, G86-011, G86-053, G86-125, H87-054, H87-055, N93-063, POWER (PR00-06009), PROMPT (PR01-06021), Q2W INITIATION (PR03-06001), EPO-NED-15Oncology trials: CISPLATIN (I88-036, OEO-U24 and OEO-U25), NON-CHEMOTHERAPY (H87-032, OEO-U20, and OEOU21), NON-CISPLATIN (I88-037, OEO-U22, and OEO-U23), AGO/NOGGO (EPO-GER-8), EP92-002, EPO-ANE-4008, EPO-CAN-15, EPO-CAN-17, EPO-CAN-20, EPO-CAN-203, EPO-CAN-303, EPO-GBR-4, EPO-GBR-7, EPO-GER-20, EPO-GER-22, EPO-GOG-191, EPO-INT-1 (2574-P-416), EPO-INT-10 (EPO-C111-457), EPO-INT-2 (CC2574-P-467), EPO-INT-3 (2574-P-034), EPO-INT-45, EPO-INT-47, EPO-INT-49, EPO-INT-50, EPO-INT-51 (EPO-CA-484), EPO-INT-76 (EPO-CA-489), EPO-J89-040 (J89-040), EPO-N93-004 (N93-004), EPO-P-169 (2574-P-169), EPO-P-174 (CC2574-P-174), MOEBUS, OBE/EPO-INT-03, PR00-03-006, PR00-27-005, PR98-27-008, PR99-11-034/044, PRI/EPO-NED-17, RTOG/PR99-03-046 (PR99-03-046), EPO-CAN-29, EPO-ANE-3010ABD trials: CC 2574-P-159, CC 2574-P-165, CC 2574-P-166, H87-017, H87-036, I88-027, I88-058Surgery trials: EPO-APO2-474, EPO-INT-34 (EPO-AP02-478), CEO-C04, H87-083, J89-001, M92-011, N93-057, PR97-19-002 (spine)MDS trials: EPO-ANE-3018 and EPOANE3021

[TSUB014.rtf] [JNJ-7472179\Z_RMP\RMP_2015\RE_RMP_2015_EU\tsub014.sas] 04FEB2016, 16:26


89

Table 15: Exposure by Age Group and Gender; All Clinical Trials Including Open ExtensionINDICATION: CHRONIC RENAL FAILURE - DIALYSISMen Women Persons Person-months Persons Person-months

Age Group (N=1149) (N=897)<18 years 2 4.21 2 6.4718 - 39 years 255 2421 187 139040 - 49 years 194 1818 142 133750 - 59 years 225 2327 183 166260 - 64 years 116 1097 91 772.865 - 69 years 118 1101 107 101770 - 74 years 124 1082 85 746.775 - 79 years 78 688.3 67 525.080 - 84 years 25 188.0 23 172.1>=85 years 10 56.51 9 87.00Missing 2 3.06 1 3.94NOTE: Thirty-three of the 2,046 patients are missing exposure data and are not included in the calculation of person-months.Chronic Renal Failure – Dialysis Trials: EP86-001 (CEO-C01), EP86-004, EPO-CAN-1, EPO-CAN-13, EPO-INT-37, EPO-INT-68, EPO-INT-77, EPO-ITA-2, ZEO-107 (CCP107P108), ZEO-121 (CC2574P121), ZEO-S01 (CCP102P103)


INDICATION: Chronic Renal Failure – PREDIALYSISMen Women Persons Person-months Persons Person-months

Age Group (N=2503) (N=3107)<18 years 0 0.00 2 10.2218 - 39 years 134 1042 210 174240 - 49 years 197 1684 272 226650 - 59 years 400 3048 522 398260 - 64 years 305 2386 379 339665 - 69 years 360 2631 397 351770 - 74 years 385 3189 441 351375 - 79 years 331 2696 373 285380 - 84 years 215 1588 285 2351>=85 years 176 1313 225 1481Missing 0 0.00 1 0.03NOTE: Two of the 5,610 patients are missing exposure data and are not included in the calculation of person-months.Chronic Renal Failure – Predialysis Trials: CHOIR (PR00-06014), EPOCKD2001, EPOCKD2002, EPO-AKD-3001, EPO-AKD-3002, EPO-AUS-14, EPO-CAN-10, EPO-INT-14, EPO-ITA-7, G86-011, G86-053, G86-125, H87-054, H87-055, N93-063, POWER (PR00-06009), PROMPT (PR01-06021), Q2W INITIATION (PR03-06001), EPO-NED-15



90

INDICATION: ONCOLOGYMen Women Persons Person-months Persons Person-months

Age Group (N=1671) (N=4156)<18 years 137 561.1 107 581.418 - 39 years 48 162.7 438 279340 - 49 years 146 423.5 916 551950 - 59 years 352 1066 1266 805560 - 64 years 271 823.4 557 337965 - 69 years 302 935.8 382 203370 - 74 years 239 720.8 308 134975 - 79 years 120 320.9 132 606.780 - 84 years 41 116.2 37 132.4>=85 years 15 26.38 13 29.37Missing 0 0.00 0 0.00NOTE: Five of the 5,827 patients are missing exposure data and are not included in the calculation of person-months.Oncology Trials: CISPLATIN (I88-036, OEO-U24 and OEO-U25), NON-CHEMOTHERAPY (H87-032, OEO-U20, and OEOU21), NON-CISPLATIN (I88-037, OEO-U22 and OEO-U23), AGO/NOGGO (EPO-GER-8), EP92-002, EPO-ANE-4008, EPO-CAN-15, EPO-CAN-17, EPO-CAN-20, EPO-CAN-203, EPO-CAN-303, EPO-GBR-4, EPO-GBR-7, EPO-GER-20, EPO-GER-22, EPO-GOG-191, EPO-INT-1 (2574-P-416), EPO-INT-10 (EPO-C111-457), EPO-INT-2 (CC2574-P-467), EPO-INT-3 (2574-P-034), EPO-INT-45, EPO-INT-47, EPO-INT-49, EPO-INT-50, EPO-INT-51 (EPO-CA-484), EPO-INT-76 (EPO-CA-489), EPO-J89-040 (J89-040), EPO-N93-004 (N93-004), EPO-P-169 (2574-P-169), EPO-P-174 (CC2574-P-174), MOEBUS, OBE/EPO-INT-03, PR00-03-006, PR00-27-005, PR98-27-008, PR99-11-034/044, PRI/EPO-NED-17, RTOG/PR99-03-046 (PR99-03-046), EPO-ANE-3010, EPO-CAN-29


INDICATION:AUTOLOGOUS BLOOD DONATIONMen Women Persons Person-months Persons Person-months

Age Group (N=143) (N=259)<18 years 3 1.77 3 1.8418 - 39 years 24 27.66 28 29.2140 - 49 years 20 21.88 21 19.0250 - 59 years 35 39.29 63 62.2960 - 64 years 27 23.23 43 36.4765 - 69 years 15 11.33 42 29.2770 - 74 years 14 8.97 33 24.5475 - 79 years 3 1.77 17 10.7180 - 84 years 2 1.22 8 4.90>=85 years 0 0.00 1 0.66Missing 0 0.00 0 0.00NOTE: Two women (1 in the 18- to 39-year age group and 1 in the 50- to 59-year age group) are missing exposure data and are not included in the calculation of person-monthsABD Trials: CC 2574-P-159, CC 2574-P-165, CC 2574-P-166, H87-017, H87-036, I88-027, I88-058



91

INDICATION: SURGERYMen Women Persons Person-months Persons Person-months

Age Group (N=378) (N=974)<18 years 0 - 0 -18 - 39 years 24 16.66 52 32.1340 - 49 years 34 16.95 88 58.8150 - 59 years 68 30.39 159 101.760 - 64 years 65 29.70 123 81.2865 - 69 years 75 38.34 157 99.2970 - 74 years 41 25.66 161 94.5275 - 79 years 43 25.17 130 84.2480 - 84 years 21 12.39 77 45.57>=85 years 6 3.58 27 16.43Missing 1 0.00 0 0.00NOTE: Forty-one of the 1,352 patients are missing exposure data and are not included in the calculation of person-months.Surgery Trials: EPO-APO2-474, EPO-INT-34 (EPO-AP02-478), CEO-C04, H87-083, J89-001, M92-011, N93-057, PR97-19-002 (spine)


INDICATION: MDS Men Women Persons Person-months Persons Person-months

Age Group (N=63) (N=39)<18 years 0 - 0 -18 - 39 years 0 - 0 -40 - 49 years 1 1.64 1 5.4950 - 59 years 3 10.48 1 8.3460 - 64 years 4 24.41 3 22.1465 - 69 years 8 59.47 4 22.7770 - 74 years 15 102.18 12 76.3275 - 79 years 16 103.98 7 53.1680 - 84 years 8 52.01 8 65.12>=85 years 8 42.35 3 27.73Missing 0 0.00 0 0.00MDS Trials: EPO-ANE-3018 and EPOANE3021



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Table 16: Exposure by Age Group and Gender (Totals); All Clinical Trials Including Open Extension

INDICATION: ALLMen Women Persons Person-months Persons Person-months

Age Group (N=5907) (N=9432)<18 years 142 567.10 114 599.9518 - 39 years 485 3669.78 915 5986.5340 - 49 years 592 3965.40 1440 9205.8550 - 59 years 1083 6521.07 2194 13871.2460 - 64 years 788 4383.28 1196 7688.1565 - 69 years 878 4777.46 1089 6718.8570 - 74 years 818 5128.71 1040 5803.4075 - 79 years 591 3836.29 726 4132.7380 - 84 years 312 1957.95 438 2771.02>=85 years 215 1442.04 278 1642.35Missing 3 3.06 2 3.98NOTE: Eighty-three of the 15,339 patients are missing exposure data and are not included in the calculation of person-months.Chronic Renal Failure – Dialysis Trials: EP86-001 (CEO-C01), EP86-004, EPO-CAN-1, EPO-CAN-13, EPO-INT-37, EPO-INT-68, EPO-INT-77, EPO-ITA-2, ZEO-107 (CCP107P108), ZEO-121 (CC2574P121), ZEO-S01 (CCP102P103)Chronic Renal Failure – Predialysis Trials: CHOIR (PR00-06014), EPOCKD2001, EPOCKD2002, EPO-AKD-3001, EPO-AKD-3002, EPO-AUS-14, EPO-CAN-10, EPO-INT-14, EPO-ITA-7, G86-011, G86-053, G86-125, H87-054, H87-055, N93-063, POWER (PR00-06009), PROMPT (PR01-06021), Q2W INITIATION (PR03-06001), EPO-NED-15.Oncology Trials: CISPLATIN (I88-036, OEO-U24 and OEO-U25), NON-CHEMOTHERAPY (H87-032, OEO-U20, and OEOU21), NON-CISPLATIN (I88-037, OEO-U22 and OEO-U23), AGO/NOGGO (EPO-GER-8), EP92-002, EPO-ANE-4008, EPO-CAN-15, EPO-CAN-17, EPO-CAN-20, EPO-CAN-203, EPO-CAN-303, EPO-GBR-4, EPO-GBR-7, EPO-GER-20, EPO-GER-22, EPO-GOG-191, EPO-INT-1 (2574-P-416), EPO-INT-10 (EPO-C111-457), EPO-INT-2 (CC2574-P-467), EPO-INT-3 (2574-P-034), EPO-INT-45, EPO-INT-47, EPO-INT-49, EPO-INT-50, EPO-INT-51 (EPO-CA-484), EPO-INT-76 (EPO-CA-489), EPO-J89-040 (J89-040), EPO-N93-004 (N93-004), EPO-P-169 (2574-P-169), EPO-P-174 (CC2574-P-174), MOEBUS, OBE/EPO-INT-03, PR00-03-006, PR00-27-005, PR98-27-008, PR99-11-034/044, PRI/EPO-NED-17, RTOG/PR99-03-046 (PR99-03-046), EPO-CAN-29, EPO-ANE-3010ABD Trials: CC 2574-P-159, CC 2574-P-165, CC 2574-P-166, H87-017, H87-036, I88-027, I88-058Surgery Trials: EPO-APO2-474, EPO-INT-34 (EPO-AP02-478), CEO-C04, H87-083, J89-001, M92-011, N93-057, PR97-19-002 (spine)MDS Trials: EPO-ANE-3018 and EPOANE3021


Table 17: Exposure by Ethnic and Racial Origin; All Clinical Trials Including Open ExtensionINDICATION: CHRONIC RENAL FAILURE - DIALYSIS

Race Persons (N=2046) Person-months White 1800 16205.50Black or African American 68 862.03Asian 75 711.36American Indian or Alaska Native 6 89.53Hispanic or Latino 7 89.79Other a 90 548.01Missing 0 0.00Total 2046 18506.22a Other races include ABORIGINAL (2), ARABIAN (1), E. INDIAN (1), EAST-INDIAN (4), FILIPINO (2), GYPSY (1), JAMAICAN (1), LEBANESE (1), MAGHREB (1), MACHREB (1), MAGHREBIN (1), MAROCCAN (1), MARTINIQUAISE (1), METIS (1), NATIVE CANADIAN (1), PAKISTANI (1), PORTUGUESE (2), TURC (1), TURKISCH (1), VIETNAMESE (1), WESTINDIAN (1) and MISSING (63).NOTE: Thirty-three of the 2,046 patients are missing exposure data and are not included in the calculation of person-months.Chronic Renal Failure – Dialysis Trials: EP86-001 (CEO-C01), EP86-004, EPO-CAN-1, EPO-CAN-13, EPO-INT-37, EPO-INT-68, EPO-INT-77, EPO-ITA-2, ZEO-107 (CCP107P108), ZEO-121 (CC2574P121), ZEO-S01 (CCP102P103)


INDICATION: CHRONIC RENAL FAILURE - PREDIALYSISRace Persons (N=5610) Person-months White 3406 27622.60Black or African American 1516 11805.34


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Asian 151 1074.33American Indian or Alaska Native 15 120.28Hispanic or Latino 459 3649.64Other a 63 416.89Missing 0 0.00Total 5610 44689.08a Other races include ABORIGINAL (1), AFRICAN AMERICAN/ARABIC (1), ARABIC (1), ARMENIAN (1), ARMENIAN ASYRIAN (1), ASIAN/CAUCASIAN (1), BRAZILIAN (1), BROWN (1), COOK ISLAND (2), CUMBODIAN (1), EAST-INDIAN (3), GUYANESE (1), INDIAN (4), INDIAN (EGYPTIAN) (1), JORDANIAN (1), MAORI (3), MIDDLE EASTERN (1), NATIVE HAWAIIAN OR OTHER PACIFIC ISLANDER (1), NATIVE HAWAIIAN OR PACIFIC ISLANDER (2), PALASTINIAN (1), PHILIPINO (2), PHILLIPANO (1), PHILLIPINO (1), PORTUGESE (1), RUSSIAN (3), SAMOAN (1), SAMON (1) and MISSING (24).NOTE: Two of the 5,610 patients are missing exposure data and are not included in the calculation of person-months.Chronic Renal Failure – Predialysis Trials: CHOIR (PR00-06014), EPOCKD2001, EPOCKD2002, EPO-AKD-3001, EPO-AKD-3002, EPO-AUS-14, EPO-CAN-10, EPO-INT-14, EPO-ITA-7, G86-011, G86-053, G86-125, H87-054, H87-055, N93-063, POWER (PR00-06009), PROMPT (PR01-06021), Q2W INITIATION (PR03-06001), EPO-NED-15


INDICATION: ONCOLOGYRace Persons (N=5827) Person-months White 3772 19561.03Black or African American 145 430.42Asian 366 4397.96American Indian or Alaska Native 3 6.37Hispanic or Latino 29 100.47Other a 52 487.36Missing 1460 4650.84Total 5827 29634.46a Other races include AFGHAN(1), ANTILLEAN(2), ARAB(1), ASIAN-FILIPINO(2), CARIBBEAN (1), COLOURED(2), EAST-INDIAN(3), EGYPTIAN(1), FIJIAN(1), FIRST NATIONS (NATIVE)(1), GUATEMALAN(1), GYPSY(2), HALF-CASTE(3), HISPANIC(12), INDIAN(1), MESTIZA(1), MIXED RACE(3), MIXED- ASIAN/AFRICAN(1), MOTHER-ASIAN/FATHER CAUCASIAN(1), NATIVE HAWAIIAN(1), PHILIPINO(1), PORTUGESE(1), SURINAM(1), TRINIDADIAN(1) and MISSING (7).NOTE: Five of the 5,827 patients are missing exposure data and are not included in the calculation of person-months.Oncology Trials: CISPLATIN (I88-036, OEO-U24 and OEO-U25), NON-CHEMOTHERAPY (H87-032, OEO-U20, and OEOU21), NON-CISPLATIN (I88-037, OEO-U22 and OEO-U23), AGO/NOGGO (EPO-GER-8), EP92-002, EPO-ANE-4008, EPO-CAN-15, EPO-CAN-17, EPO-CAN-20, EPO-CAN-203, EPO-CAN-303, EPO-GBR-4, EPO-GBR-7, EPO-GER-20, EPO-GER-22, EPO-GOG-191, EPO-INT-1 (2574-P-416), EPO-INT-10 (EPO-C111-457), EPO-INT-2 (CC2574-P-467), EPO-INT-3 (2574-P-034), EPO-INT-45, EPO-INT-47, EPO-INT-49, EPO-INT-50, EPO-INT-51 (EPO-CA-484), EPO-INT-76 (EPO-CA-489), EPO-J89-040 (J89-040), EPO-N93-004 (N93-004), EPO-P-169 (2574-P-169), EPO-P-174 (CC2574-P-174), MOEBUS, OBE/EPO-INT-03, PR00-03-006, PR00-27-005, PR98-27-008, PR99-11-034/044, PRI/EPO-NED-17, RTOG/PR99-03-046 (PR99-03-046), EPO-ANE-3010, EPO-CAN-29


INDICATION:AUTOLOGOUS BLOOD DONATIONRace Persons(N=402) Person-months White 372 338.07Black or African American 24 14.29Asian 0 0.00American Indian or Alaska Native 0 0.00Hispanic or Latino 0 0.00Other a 6 3.68Missing 0 0.00Total 402 356.04a Other races include INDIAN (1) and MISSING (5).NOTE: Two women (1 in the 18- to 39-year age group and 1 in the 50- to 59-year age group) are missing exposure data and are not included in the calculation of person-months.ABD Trials: CC 2574-P-159, CC 2574-P-165, CC 2574-P-166, H87-017, H87-036, I88-027, I88-058



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INDICATION:SURGERYRace Persons (N=1352) Person-months White 1148 695.89Black or African American 173 100.86Asian 5 1.91American Indian or Alaska Native 0 0.00Hispanic or Latino 15 9.30Other a 11 4.83Missing 0 0.00Total 1352 812.78a Other races include CAPE VERDIAN (1) and MISSING (10).NOTE: Forty-one of the 1,352 patients are missing exposure data and are not included in the calculation of person-months.Surgery Trials: EPO-APO2-474, EPO-INT-34 (EPO-AP02-478), CEO-C04, H87-083, J89-001, M92-011, N93-057, PR97-19-002 (spine)


INDICATION: MDSRace Persons (N=102) Person-months White 17 73.89Black or African American 0 0.00Asian 0 0.00American Indian or Alaska Native 0 0.00Hispanic or Latino 0 0.00Other 0 0.00Missing 85 603.70Total 102 677.59MDS Trials: EPO-ANE-3018 and EPOANE3021



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Table 18: Exposure by Ethnic and Racial Origin (Totals); All Clinical Trials Including Open ExtensionINDICATION:ALL

Race Persons (N=15339) Person-months White 10515 64496.99Black or African American 1926 13212.94Asian 597 6185.56American Indian or Alaska Native 24 216.18Hispanic or Latino 510 3849.20Other 222 1460.76Missing 1545 5254.54Total 15339 94676.17NOTE: Eight-three of the 15,339 patients are missing exposure data and are not included in the calculation of person-months.Chronic Renal Failure – Dialysis Trials: EP86-001 (CEO-C01), EP86-004, EPO-CAN-1, EPO-CAN-13, EPO-INT-37, EPO-INT-68, EPO-INT-77, EPO-ITA-2, ZEO-107 (CCP107P108), ZEO-121 (CC2574P121), ZEO-S01 (CCP102P103)Chronic Renal Failure – Predialysis Trials: CHOIR (PR00-06014), EPOCKD2001, EPOCKD2002, EPO-AKD-3001, EPO-AKD-3002, EPO-AUS-14, EPO-CAN-10, EPO-INT-14, EPO-ITA-7, G86-011, G86-053, G86-125, H87-054, H87-055, N93-063, POWER (PR00-06009), PROMPT (PR01-06021), Q2W INITIATION (PR03-06001), EPO-NED-15.Oncology Trials: CISPLATIN (I88-036, OEO-U24 and OEO-U25), NON-CHEMOTHERAPY (H87-032, OEO-U20, and OEOU21), NON-CISPLATIN (I88-037, OEO-U22 and OEO-U23), AGO/NOGGO (EPO-GER-8), EP92-002, EPO-ANE-4008, EPO-CAN-15, EPO-CAN-17, EPO-CAN-20, EPO-CAN-203, EPO-CAN-303, EPO-GBR-4, EPO-GBR-7, EPO-GER-20, EPO-GER-22, EPO-GOG-191, EPO-INT-1 (2574-P-416), EPO-INT-10 (EPO-C111-457), EPO-INT-2 (CC2574-P-467), EPO-INT-3 (2574-P-034), EPO-INT-45, EPO-INT-47, EPO-INT-49, EPO-INT-50, EPO-INT-51 (EPO-CA-484), EPO-INT-76 (EPO-CA-489), EPO-J89-040 (J89-040), EPO-N93-004 (N93-004), EPO-P-169 (2574-P-169), EPO-P-174 (CC2574-P-174), MOEBUS, OBE/EPO-INT-03, PR00-03-006, PR00-27-005, PR98-27-008, PR99-11-034/044, PRI/EPO-NED-17, RTOG/PR99-03-046 (PR99-03-046), EPO-CAN-29, EPO-ANE-3010ABD Trials: CC 2574-P-159, CC 2574-P-165, CC 2574-P-166, H87-017, H87-036, I88-027, I88-058Surgery Trials: EPO-APO2-474, EPO-INT-34 (EPO-AP02-478), CEO-C04, H87-083, J89-001, M92-011, N93-057, PR97-19-002 (spine)MDS Trials: EPO-ANE-3018 and EPOANE3021



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Table 19: Exposure by Special Population; All Clinical Trials Including Open ExtensionINDICATION: CHRONIC RENAL FAILURE - DIALYSIS

Population Category at Baseline Persons Person-months Total (N=2046)Hepatic Impairment (n=907)ALT





ALT=alanine aminotransfersase; AST=aspartate aminotransferase; ULN=upper limit of normal; x=timesPerson-months may be underestimated due to missing exposure data.Of 2,046 patients in the Chronic Renal Failure – Adult Haemodialysis dataset, 907 patients had at least one non-missing hepatic ALT, AST, BILIRUBIN or alkaline phosphatase measurement. For each parameter measured, some of the 907 patients did not have data available and are counted as missing.Chronic Renal Failure – Dialysis Trials: EP86-001 (CEO-C01), EP86-004, EPO-CAN-1, EPO-CAN-13, EPO-INT-37, EPO-INT-68, EPO-INT-77, EPO-ITA-2, ZEO-107 (CCP107P108), ZEO-121 (CC2574P121), ZEO-S01 (CCP102P103)



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INDICATION: CHRONIC RENAL FAILURE - PREDIALYSISPopulation Category at Baseline Persons Person-months Total (N=5610)Hepatic Impairment (n=3796)ALT





ALT=alanine aminotransfersase; AST=aspartate aminotransferase; ULN=upper limit of normal; x=timesPerson-months may be underestimated due to missing exposure data.Of 5,610 patients in the Chronic Renal Failure – Adult Predialysis dataset, 3,796 patients had at least one non-missing hepatic ALT, AST, BILIRUBIN or alkaline phosphatase measurement. For each parameter measured, some of the 3,796 patients did not have data available and are counted as missing.Chronic Renal Failure – Predialysis Trials: CHOIR (PR00-06014), EPOCKD2001, EPOCKD2002, EPO-AKD-3001, EPO-AKD-3002, EPO-AUS-14, EPO-CAN-10, EPO-INT-14, EPO-ITA-7, G86-011, G86-053, G86-125, H87-054, H87-055, N93-063, POWER (PR00-06009), PROMPT (PR01-06021), Q2W INITIATION (PR03-06001), EPO-NED-15



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INDICATION: ONCOLOGYPopulation Category at Baseline Persons Person-months







ALT=alanine aminotransferase; AST=aspartate aminotransferase; CrCl=creatinine clearance; N/n=number; ULN=upper limit of normal; x=timesPerson-months may be underestimated due to missing exposure data.a Of the 5,827 patients in the oncology dataset, 3,496 patients had data measuring hepatic impairment. For each parameter measured, some patients did not have data available and are counted as missing.b Of the 3,740 patients with CrCl data, only 1,932 patients were categorized as mild, moderate, or severe with respect to renal impairment. The remaining 1,808 patients were normal or missing baseline CrCl.Oncology studies: CISPLATIN (I88-036, OEO-U24, and OEO-U25), NON-CHEMOTHERAPY (H87-032, OEO-U20, and OEOU21), NON-CISPLATIN (I88-037, OEO-U22, and OEO-U23), AGO/NOGGO (EPO-GER-8), EP92-002, EPO-ANE-4008, EPO-CAN-15, EPO-CAN-17, EPO-CAN-20, EPO-CAN-203, EPO-CAN-303, EPO-GBR-4, EPO-GBR-7, EPO-GER-20, EPO-GER-22, EPO-GOG-191, EPO-INT-1 (2574-P-416), EPO-INT-10 (EPO-C111-457), EPO-INT-2 (CC2574-P-467), EPO-INT-3 (2574-P-034), EPO-INT-45, EPO-INT-47, EPO-INT-49, EPO-INT-50, EPO-INT-51 (EPO-CA-484), EPO-INT-76 (EPO-CA-489), EPO-J89-040 (J89-040), EPO-N93-004 (N93-004), EPO-P-169 (2574-P-169), EPO-P-174 (CC2574-P-174), MOEBUS, OBE/EPO-INT-03, PR00-03-006, PR00-27-005, PR98-27-008, PR99-11-034/044, PRI/EPO-NED-17, RTOG/PR99-03-046 (PR99-03-046), EPO-ANE-3010, EPO-CAN-29

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INDICATION:AUTOLOGOUS BLOOD DONATIONPopulation Category at Baseline Persons Person-months Total (N=402)Hepatic Impairmenta (n=398)ALT






ABD=autologous blood donation; ALT=alanine aminotransfersase; AST=aspartate aminotransferase; CrCl=creatinine clearance; ULN=upper limit of normal; x=timesPerson-months may be underestimated due to missing exposure data.a Of the 402 patients in the ABD dataset, 398 patients had data measuring hepatic impairment. For each parameter measured, some patients did not have data available and are counted as missing.b Of the 390 patients with CrCl data, only 186 patients were categorized as mild, moderate, or severe with respect to renal impairment. The remaining 204 patients were normal or missing baseline CrCl.ABD Trials: CC 2574-P-159, CC 2574-P-165, CC 2574-P-166, H87-017, H87-036, I88-027, I88-058



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INDICATION:SURGERYPopulation Category at Baseline Persons Person-months Total (N=1352)Hepatic Impairmenta (n=973)ALT






ALT=alanine aminotransfersase; AST=aspartate aminotransferase; CrCl=creatinine clearance; ULN=upper limit of normal; x=timesPerson-months may be underestimated due to missing exposure data.a Of the 1,352 patients in the Surgery dataset, 973 patients had data measuring hepatic impairment. For each parameter measured, some patients did not have data available and are counted as missing.b Of the 1,303 patients with CrCl data, only 723 patients were categorized as mild, moderate, or severe with respect to renal impairment. The remaining 580 patients were normal or missing baseline CrCl.Surgery Trials: EPO-APO2-474, EPO-INT-34 (EPO-AP02-478), CEO-C04, H87-083, J89-001, M92-011, N93-057, PR97-19-002 (spine)



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INDICATION: MDSPopulation Category at Baseline Persons Person-months Total (N=102)Hepatic Impairment (n=99)ALT






ALT=alanine aminotransfersase; AST=aspartate aminotransferase; CrCl=creatinine clearance; MDS=myelodysplastic syndrome; ULN=upper limit of normal; x=timesPerson-months may be underestimated due to missing exposure data.a Of the 102 patients in the MDS dataset, 99 patients had data measuring hepatic impairment. For each parameter measured, some patients did not have data available and are counted as missing.b Of the 101 patients with CrCl data, only 68 patients were categorized as mild, moderate, or severe with respect to renal impairment. The remaining 33 patients were normal or missing baseline CrCl.MDS Trials: EPO-ANE-3018 and EPOANE3021



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Table 20: Exposure by Special Population (Totals); All Clinical Trials Including Open Extension

INDICATION:ALLPopulation Category at Baseline Persons Person-months








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Table 20: Exposure by Special Population (Totals); All Clinical Trials Including Open Extension

ALT=alanine aminotransferase; AST=aspartate aminotransferase; CrCl=creatine clearance; N/n=number; ULN=upper limit of normal; x-timesPerson-months may be underestimated due to missing exposure data.a Of the 15,339 patients, 9,669 patients had data measuring hepatic impairment. For each parameter measured, some patients did not have data available and are counted as missing.For Renal Impairment, only trials associated with oncology, ABD, surgery, and MDS indications are included.b Of the 5,534 patients with CrCl data, only 2,909 patients were categorized as mild, moderate, or severe with respect to renal impairment. The remaining 2,625 patients were normal or missing baseline CrCl.Chronic Renal Failure – Dialysis Studies: EP86-001 (CEO-C01), EP86-004, EPO-CAN-1, EPO-CAN-13, EPO-INT-37, EPO-INT-68, EPO-INT-77, EPO-ITA-2, ZEO-107 (CCP107P108), ZEO-121 (CC2574P121), ZEO-S01 (CCP102P103)Chronic Renal Failure – Predialysis Studies: CHOIR (PR00-06014), EPOCKD2001, EPOCKD2002, EPO-AKD-3001, EPO-AKD-3002, EPO-AUS-14, EPO-CAN-10, EPO-INT-14, EPO-ITA-7, G86-011, G86-053, G86-125, H87-054, H87-055, N93-063, POWER (PR00-06009), PROMPT (PR01-06021), Q2W INITIATION (PR03-06001), EPO-NED-15.Oncology Studies: CISPLATIN (I88-036, OEO-U24 and OEO-U25), NON-CHEMOTHERAPY (H87-032, OEO-U20, and OEOU21), NON-CISPLATIN (I88-037, OEO-U22, and OEO-U23), AGO/NOGGO (EPO-GER-8), EP92-002, EPO-ANE-4008, EPO-CAN-15, EPO-CAN-17, EPO-CAN-20, EPO-CAN-203, EPO-CAN-303, EPO-GBR-4, EPO-GBR-7, EPO-GER-20, EPO-GER-22, EPO-GOG-191, EPO-INT-1 (2574-P-416), EPO-INT-10 (EPO-C111-457), EPO-INT-2 (CC2574-P-467), EPO-INT-3 (2574-P-034), EPO-INT-45, EPO-INT-47, EPO-INT-49, EPO-INT-50, EPO-INT-51 (EPO-CA-484), EPO-INT-76 (EPO-CA-489), EPO-J89-040 (J89-040), EPO-N93-004 (N93-004), EPO-P-169 (2574-P-169), EPO-P-174 (CC2574-P-174), MOEBUS, OBE/EPO-INT-03, PR00-03-006, PR00-27-005, PR98-27-008, PR99-11-034/044, PRI/EPO-NED-17, RTOG/PR99-03-046 (PR99-03-046), EPO-CAN-29, EPO-ANE-3010ABD Studies: CC 2574-P-159, CC 2574-P-165, CC 2574-P-166, H87-017, H87-036, I88-027, I88-058Surgery Studies: EPO-APO2-474, EPO-INT-34 (EPO-AP02-478), CEO-C04, H87-083, J89-001, M92-011, N93-057, PR97-19-002 (spine)MDS Studies: EPO-ANE-3018 and EPOANE3021

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Module SIV: Populations Not Studied in Clinical Trials











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Important exclusion criteria that limited the participation of specific subpopulations of patients

within the expected target indication across Phase 2/3 clinical trials are listed in Modules SIV.1

and SIV.2. The implications of limited experience with EPREX in populations typically

under-represented in the clinical trial development programme(s) with respect to predicting the

safety of EPREX in the marketplace are discussed in Module SIV.3.

SIV.1. Limitations of Adverse Drug Reaction Detection Common to All Clinical Trial Development Programmes

Ability to detectadverse reactions

Limitationof trial programme

Discussion ofimplications for target population

Which are rare (it may be appropriate to choose other ADR frequencies)

With an overall exposure to EPREX of an estimated 15,339 patients in the clinical trial programme, rare ADRs (1/10,000 and <1/1,000), some of which may be potentially of medical significance, may not have been detected in clinical trials.

Postmarketing surveillance and signal detection are used to detect rare ADRs.

Due to prolonged exposure Negligible limitations due to the long durations of treatment, especially in the CRF predialysis population with treatment for up to 48 months and exposure of >44,000 person-months. Over 200 patients have been treated in clinical trials for ≥24 months.

There does not appear to be any unknown ADRs due to long-term exposure to EPREX.


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Ability to detectadverse reactions

Limitationof trial programme

Discussion ofimplications for target population

Due to cumulative effects The half-life of epoetin alfa following multiple doses viaIV administration is approximately 4 hours in healthy patients. The half-life for the SC route is estimated to be approximately 24 hours in healthy patients. Patients also produce endogenous erythropoietin that cannot be distinguished from epoetin alfa using standard methods. Therefore, it is difficult to ascertain what constitutes a cumulative effect of exogenous EPREX administration. It is recommended that the dose is titrated according to HGBconcentrations, which would minimise the risk of cumulative effects.

No additional adverse cumulative effects have been seen during exposure to EPREX.

Which have a long latency Studies to evaluate long latency have not been conducted. Therefore, ADRs with long latency may have not been detected.

Postmarketing pharmacovigilance surveillance and signal detection are used to detect events with a long latency.

ADR=adverse drug reaction; CRF=chronic renal failure; HGB=haemoglobin; IV=intravenous; SC=subcutaneous


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SIV.2. Effect of Exclusion Criteria in the Clinical Trial Development Plan

Exclusion Criteria That Will Remain as Contraindications

Criteria Implications for target population

Pure red cell aplasia Pure red cell aplasia is a very rare and serious condition and was discovered through postauthorisation surveillance. Patients who develop PRCA following treatment with any erythropoietin should not receive EPREX or any other erythropoietin and will have alternative treatment options for anaemia.

Uncontrolled hypertension Hypertension is the most frequent ADR during treatment with epoetin alfa. Patients with uncontrolled hypertension can experience hypertensive crisis therefore, hypertension should be controlled first before starting treatment with EPREX.

Known hypersensitivity to epoetin alfa or any of its excipients

Patients with known hypersensitivity to epoetin alfa or any of its excipients have alternative treatment options for the treatment of anaemia.

Surgery

Surgery patients who are unable to receive appropriate antithrombotic therapy during surgery and the postoperative hospital course

Surgery patients who for any reason cannot receive adequate antithrombotic prophylaxis during surgery and the postoperative hospital course will have alternative treatment options for the treatment of anaemia.

Severe cardiac or cerebral disease

Patients with severe cardiac or cerebral disease will have alternative treatment options for the treatment of anaemia.


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Exclusion Criteria That are NOT Proposed to Remain as Contraindications

CriteriaReason for being an exclusion criterion

Justification for not being a contraindication

Indication: Chronic Renal Failure

Androgen, corticosteroid, or immunosuppressant therapy

These medications are known to have potential to have an effect on HGB.

These medications were excluded in the early phase of the clinical development programme; however, EPREX is now used in patients who have undergone renal transplantation and are receiving immunosuppressant therapy.

Sickle cell anaemia Sickle cells cause chronically low RBC production, resulting in anaemia.

Trials have been performed on the efficacy and safety of EPREX forthe treatment of anaemia in patients with sickle cell anaemia.

Clinically evident aluminium intoxication

Aluminium intoxication can be caused by dialysis and may lead to aluminium-induced bone disease, microcytic anaemia, and neurologic dysfunction (encephalopathy)

The mechanism of action of EPREX is not considered to increase the severity of aluminium intoxication.

Indication: Cancer

Pre-trial HGB >10.5 g/dL No clinically significant effect on reduction of transfusion needs.

Controlled clinical trials have not shown significant benefits attributable to the administration of epoetins when HGB concentration is increased beyond the level necessary to control symptoms of anaemia and to avoid blood transfusion.

History of seizures Potential for encephalopathy. Overall, seizure was reported as an uncommon ADR in EPREX clinical trials. It is recommended that EPREX should be used with caution in patients with epilepsy, history of seizures, or medical conditions associated with a predisposition to seizure activity such as central nervous system infections and brain metastases.


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Active infection It is common clinical practice not to include patients with uncontrolled and potentially life-threatening infections in trials.

The mechanism of action of EPREX is not considered to increase the severity of infections.

Acute blood loss (of any kind) Needs to be treated by other means; anaemia caused by these events will not benefit from EPREX treatment.

All other causes of anaemia, including blood loss, should be evaluated and treated prior to initiating therapy with epoetin alfa, and when deciding to increase the dose. Treatment with EPREX does not immediately increase HGB in acute situations.

Pregnancy, nursing, or planning a pregnancy (both men and women) within 18 months of enrolment

It is common clinical practicenot to include pregnant women in clinical trials.

There are no adequate and well-controlled trials in pregnant women. Findings in animal toxicology studies were interpreted as being secondary to decreased maternal body weight gain when given in weekly doses of approximately 20 times the recommended human dose; therefore, the significance to humans is unknown when given at therapeutic dose levels (see Module SII) It is not known whether exogenous epoetin alfa is excreted in human milk. Epoetin alfa should be used with caution in nursing women. A decision on whether to continue/discontinue breastfeeding or to continue/discontinue therapy with epoetin alfa should be made taking into account the benefit of breastfeeding to the child and the benefit of epoetin alfa therapy to the woman.


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Indication: Surgery

Evidence of haemolysis or gastrointestinal bleeding

Needs to be treated by other means; anaemia caused by these events will not benefit from EPREX treatment.

All other causes of anaemia, including blood loss, should be evaluated and treated prior to initiating therapy with epoetin alfa, and when deciding to increase the dose. Treatment with EPREX does not immediately increase HGB in acute situations.

Active infection Increased risk of infection in surgery.

The mechanism of action of EPREX is not considered to increase the severity of infections.

ADR=adverse drug reaction; HGB=haemoglobin; PRCA=pure red cell aplasia; RBC=red blood cell

SIV.3. Limitations in Respect to Populations Typically Under-represented in Clinical Trial Development Programme(s)

Children

EPREX is indicated only for the treatment of anaemia associated with CRF in paediatric patients

on haemodialysis. A total of 256 children (patients <18 years of age) have been exposed to

EPREX in all clinical trials.

Risks associated with use of EPREX in children, including the potential for off-label paediatric

use, are discussed in Module SVI.6.2, Potential for Paediatric Off-label Use.

Elderly

Of the 15,339 patients in clinical trials of EPREX (with patient-level data available for this

database), 6,384 (42%) were 65 years of age and older, while 2,560 (17%) were 75 years of age

and older.

Pregnant or Breastfeeding Women

There are no adequate and well-controlled trials in pregnant women. Findings in animal

toxicology studies were interpreted as being secondary to decreased maternal body weight gain

when given in weekly doses of approximately 20 times the recommended human dose; therefore,

the significance to humans is unknown when given at therapeutic dose levels (see Module SII). It

is recommended that epoetin alfa should be used in pregnancy only if the potential benefit

outweighs the potential risk to the foetus.

It is not known whether exogenous epoetin alfa is excreted in human milk. Epoetin alfa should

be used with caution in nursing women. A decision to continue/discontinue breast-feeding or to

continue/discontinue therapy with epoetin alfa should be made taking into account the benefit of

breast-feeding to the child and the benefit of epoetin alfa therapy to the woman.


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The use of epoetin alfa is not recommended in lactating surgical patients participating in an

ABD programme.

Patients with Hepatic Impairment

The safety of epoetin alfa has not been established in patients with hepatic dysfunction. A total

of 140 patients known to have hepatic impairment at baseline (alanine aminotransferase

>2.5 upper limit of normal [ULN]) were exposed to EPREX in clinical trials. One hundred

thirty-five patients with aspartate aminotransferase levels (AST) >2.5 ULN at baseline,

268 patients with bilirubin levels >1.5 ULN at baseline, and 289 patients with alkaline

phosphatase levels >2.5 ULN at baseline were exposed to EPREX in clinical trials. No trials

have been conducted specifically in patients with hepatic dysfunction.

Patients With Other Relevant Comorbidity

Cardiovascular

Patients with significant cardiovascular comorbidities were excluded in the early (pivotal) trials

in the clinical trial programme, but were included in trials conducted afterwards. These

post-approval trials contributed significantly to the understanding of the safety profile for the

CRF indication; the Correction of Haemoglobin and Outcomes in Renal Insufficiency

(CHOIR, PR00-06-014) trial, for example, evaluated 1,432 anaemic patients with CRF. Some of

the patients in this trial had comorbidities such as MI, stroke, and CHF hospitalisations. In

response to questions from the CHMP, the marketing authorisation holder (MAH) evaluated

pooled data from 27 Company-sponsored studies (n=7,254 patients) designed to evaluate

efficacy or safety of epoetin alfa treatment in adults with CKD. All analyses were performed

both with and without adjustment for baseline risk factors such as comorbidities

(including medical history of hypertension, coronary artery disease, heart failure,

cerebrovascular disease, and peripheral vascular disease). There were few interactions at the

0.1 level of significance between any HGB or dose variable and the risk factors evaluated,

including comorbidities. The sparse occurrence of such interactions, and the lack of any

consistency across the outcomes of interest, suggests that the risk factors did not have a

noteworthy impact on the effect of mean achieved HGB, cumulative erythropoietin dose, mean

achieved HGB/cumulative erythropoietin dose, HGB variation, HGB rate of change, or

HGB response on the risks of death, cardiovascular events, cerebrovascular events, or the

composite endpoint (CHMP response 2014).

Myeloid Malignancies and Acute Leukaemias

Patients with cancer participating in clinical trials that were part of the preauthorisation cancer

clinical programme were anaemic and were receiving an aggressive platinum- or

non-platinum-containing chemotherapy regimen. Patients with myeloid malignancies were

generally excluded from the trials and therefore data are unavailable. There is currently

1 randomised, double-blind, placebo-controlled trial has been conducted (EPOANE3021) in

130 anaemic patients with MDS.


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Immunocompromised Including Transplant Patients

Renal transplant patients receiving immunosuppressive therapy have been treated with EPREX

in clinical trials.

Patients with a Disease Severity Different From the Inclusion Criteria in the Clinical Trial Population

Not applicable.

Subpopulations Carrying Known and Relevant Polymorphisms

No pharmacokinetic, pharmacodynamic, or pharmacogenomic assessments of the effect of

genetic polymorphisms on the metabolism, safety, or efficacy of EPREX have been conducted.

Patients of Different Racial and/or Ethnic Origin

Of the 15,339 patients in clinical trials of EPREX with patient-level data available, 10,515 (69%)

were White, 1,926 (13%) were Black or African American, and 1,353 (9%) were Asian,

Hispanic or Latino, American Indian or Native Alaskan, or Other. Data on ethnic and racial

origin were missing for 1,545 (10%) patients. EPREX has received market authorisation in

95 countries and the cumulative postmarketing exposure to the drug from first product launch in

1988 through 30 June 2015 is 4,575,083 PY. Therefore, the Company believes that there has

been sufficient experience in patients of all races and ethnic origins to exclude safety concerns in

any particular one.

SIV.4. Conclusions on the Populations Not Studied and Other Limitations of the Clinical Trial Development Programme

The information related to the populations not studied in clinical trials and to the other

limitations of the clinical trial development programme has been reviewed. Because of the vast

experience with EPREX since 1988 and the exposure in various populations and settings, none

of the populations that were not studied or other limitations of the clinical trial development

programme were considered to be missing information because of the amount of experience with

EPREX over the past 25 years and the exposure in various populations and settings.


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Module SV: Postauthorisation Experience











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SV.1. Action Taken by Regulatory Authorities and/or Marketing Authorisation Holders for Safety Reasons

Detailed Description of Action Taken Since Last Update (4 March 2016) to this Module

Letter to Healthcare Professionals Regarding SCARs

Background to issue Severe cutaneous adverse reactions are considered to be a class effect of all epoetins. The reactions have been more severe with long-acting epoetins. The frequency of these severe cutaneous reactions could not be calculated but they occur very rarely.

If the patient has developed a severe cutaneous adverse reaction (such as Stevens-Johnson syndrome or TEN), which is considered to be related to the use of an epoetin, the patient must never be given an epoetin again.

Evidence source Postmarketing spontaneous reports

Action taken Following a recommendation by the PRAC, the MAHs of epoetin-containing medicinal products distributed a DHPC letter to Healthcare Professionals in the EEA to inform them of the postmarketing spontaneous reports of SCARs, including Stevens-Johnson syndrome and TEN (which can be life-threatening or fatal), which have been reported in association with epoetin treatment.

The MAH decided to distribute the DHPC letter also to countries worldwide where epoetin alfa has a marketing authorisation.

Countries affected Global

Date(s) of action August 2017

Addition of Hypersensitivity/Anaphylaxis and Seizures to Risk Management Plan

Background to issue PRAC outcome of PBRER assessment of 14 April 2016: Update RMP to include hypersensitivity reactions (including anaphylactic reactions) andseizures as important identified risks. Request was made to update important identified risk of “hypertension” to “hypertension/hypertensive crisis” in a subsequent RMS Day 40 Preliminary Variation Assessment Report of 18 September 2017 and teleconference between ANSM and the MAH (on 11 December 2017).

Note: Considering the new definition provided by the GVP module V rev 2, the RMS reconsidered the above request and requested the MAH to no longer consider “hypersensitivity/anaphylaxis” and “seizures” as important identified risks for inclusion in the EU RMP on 22nd May 2018. These two risks do notindeed meet the revised criteria for “important identified risks” to be included in the EU RMP as they are well characterized and described in the SmPC, and are not subject to additional pharmacovigilance or risk minimization activities.

Evidence source Postmarketing spontaneous reports, PRAC PSUR Final Assessment Report (dated 14 April 2016), PRAC PSUR Single Assessment recommendation (also dated 14 April 2016), RMS Day 40 Preliminary Variation Assessment Report of 18 September 2017 for variation II/129, teleconference between ANSM and the MAH (on 11 December 2017), and Final Assessment Report for variation II/129 (received on 22nd May 2018).


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Detailed Description of Action Taken Since Last Update (4 March 2016) to this Module

Action taken Following PRAC outcome of PBRER assessment of 14 April 2016, and teleconference with ANSM on 11 December 2017: Submission of a Type II variation and a subsequent (current) update to the RMP.

Following the revised position from the Reference Member Statereceived on 22th May 2018: Submission of a revised RMP to remove “hypersensitivity/anaphylaxis” and “seizures” from the important identified risks.

Countries affected Countries of the EEA with a valid marketing authorisation for EPREX/ ERYPO.

Date(s) of action June 2017, January and June 2018

ANSM=L'Agence Nationale de Sécurité du Médicament et des Produits de Santé; DHPC=Dear Healthcare Provider Communication; EEA=European Economic Area; MAH=marketing authorisation holder; PBRER=Periodic Benefit-Risk Evaluation Report; PRAC= Pharmacovigilance Risk Assessment Committee of the European Medicines Agency; PSUR=Periodic Safety Update Report; RMP=risk management plan; RMS=risk management system; SCARs=severe cutaneous adverse reactions; TEN=toxic epidermal necrolysis


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Cumulative List of Significant Actions Taken for Safety Reasons

Safety Issue

Country(ies) Action taken Comment Date(s)

PRCA

European Union, Iceland, Norway, Australia, and Switzerland

A variation to amend the SmPC was submitted in all member states as of 14 September 2001. On 26 September 2001, the Company issued an advisory letter to all operating companies worldwide requesting that all relevant national marketing authorisations and prescribing information be amended. This followed a number of reported cases of PRCA and erythropoietin Ab production in CRF patients receiving the product. During the EU review process, an USR procedure was implemented to expedite the amendment to the SmPC. The USR procedure was completed on 9 November 2001.

All EU member states as well as Iceland, Norway, Australia, and Switzerland have amended their national labelling (SmPCs) in line with the USR. All other MAH European Regulatory Affairs-supported countries, where epoetin alfa is marketed, have been informed, where regulatory mechanisms exist, of the update, and regulatory actions taken as appropriate. In agreement with the EU Regulatory Authorities, the Company issued DHPC letters in all EU member states as of 19 November 2001. At the same time, the same information was communicated to all other markets in the rest of the world.

USR:9 Nov 2001DHPC letters:

19 Nov 2001

Canada A Dear Doctor Letter was issued on 26 November 2001 and a public advisory was issued on 3 December 2001 regarding reports of PRCA in CRF patients.

Dear Doctor Letter:26 Nov 2001Public Advisory: 3 Dec 2001

Switzerland On 3 May 2002, following a meeting with the MAH, the Swiss Regulatory Authority requested that the MAH issue a DHPC letters to all Swiss physicians providing an update on the reported cases of PRCA.

DHPC letter:

21 May 2002


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Safety Issue


EU, Australia, Switzerland,Canada

On 27 May 2002, the French Regulatory Authority, in its role as Reference Member State for the product in the European Union,requested that the MAH prepare a proposed DHPC letter that would provide physicians with updates on the prescribing information with respect to PRCA. The MAH provided the proposal on 31 May 2002. The Company's proposal was discussed at the EU CHMPPharmacovigilance Working Party of 10 to 12 June 2002. Following the meeting, an USR to amend the SmPCs was initiated. The USR was completed on 12 July 2002. In agreement with the EU Regulatory Authorities, the MAH issued DHPC letters in all EU member states as of 17 July 2002.

During this time, the MAH was also in discussion with the Australian, Canadian, and Swiss Regulatory Authorities and DHPC letters were subsequently issued in those countries.

EU USRcompleted:12 July 2002

EU DHPC letters circulated:17 July 2002

Australia DHPC letters:4 July 2002

Switzerland DHPC letters:31 July 2002

Canada DHPC letters:25 June 2002

Singapore

Global

The Singapore HSA distributed a DHPC letter concerning the PRCA cluster discovery. The Company, in consultation with the HSA, submitted an update to the local labelling in Singapore restricting the use of EPREX in patients with CRF by contraindicating the SCroute of administration (October 2013). This new contraindication was subsequently communicated to healthcare professionals in Singapore via a second DHPC letter from the HSA. Both DHPC letters were shared with worldwide health care authorities for their information.

Singapore:13 June 2013,2 October 2013

Global:20 June 2013,3 October 2013


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Safety Issue


Product recall

Global On 31 July 2003, the Company initiated a global voluntary and precautionary recall of specified lots of EPREX prefilled syringe products (1,000-, 2,000-, 3,000-, 4,000-, and 10,000-IU presentations) bearing lot numbers beginning with the numeric codes 01 and 02,which were still within their defined expiry date.

This recall extended to the pharmacy level and was based on the identification of small quantities of extractables in the product from the plain rubber stoppers used in the manufacture of the noted presentations.

31 July 2003

Safety in cancer patients

Australia On 5 July 2004, all epoetin alfa licence holders in Australia were requested to provide information on “the safety of recombinant erythropoietin products in cancerpatients”. This information was provided by the Company by the agreed to deadline of 19 July 2004.

The information was requested in preparation for an Australian Drug Evaluation Committee meeting on 12 to 13 August 2004.

19 July 2004

Turkey The MAH voluntarily withdrew the cancerindication for EPREX.

This was prompted by a request from the Turkish Ministry of Health to update the product labelling with recommendations concerning the use of recombinant erythropoietin in patients with cancer.

April 2005

Turkey The cancer indication reinstated and approved in Turkey on 16 November 2006.

16 November 2006


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Safety Issue


Blood clot formation

Canada DHPC letters circulated with new safety information regarding blood clot formation in cancer patients treated with epoetin alfa and similar medicines to higher than typical target HGB levels in this population.

DHPC letter:

13 October 2004

Potential tumour proliferation and TVEs

CanadaBrazilIsraelCroatia

Four countries issued DHPC letters relating to the safety issues ongoing with respect to ESAs and potential tumour proliferation and TVEs.

Canada:16 April 2007Brazil:23 April 2007Israel:10 May 2007Croatia:31 May 2007

Australia

South Africa

DHPC letters circulated relating to the ongoing safety issues of potential tumour proliferation and TVEs with respect to ESAs.

Australia:20 August 2007South Africa:5 October 2007


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Safety Issue


Correction of anaemia in cancer patients

EU On 26 June 2008, the CHMP recommended updating the product information for epoetin-containing medicines with a new warning for their use in cancer patients stating that blood transfusion should be the preferred method of correcting anaemia in cancer patients with a reasonably long-life expectancy. The EMEA circulated DHPC letters to all EU Competent Authorities for communication nationally.

The recommendations are based on the conclusion of the Scientific Advisory Group-Oncology expert meeting, which took place on 15 May 2008.

The CCDS that was updated in June 2007 is currently considered to appropriately address the CHMP recommendations. A variation to reflect these CHMP recommendations in the EU Mutual Recognition Procedure SmPC wasapproved.

DHPC letters circulatedAugust 2008

EU Mutual Recognition Procedure variation approved 24 April 2009

Impaired survival in women receiving chemotherapy for breast cancer

Dear Investigator Letter

United States

In November 2014, the Company distributed a Dear Investigator Letter to investigators to inform them of the results of Trial EPO-ANE-3010. At that time, the Informed Consent Form for the study was also updated to inform patients of the results of the study, including reconsenting of patients participating in the study.

Trial EPO-ANE-3010 failed statistically to rule out a 15% risk increase in disease progression or death; the observed degree of risk of adverse tumour outcomes was consistent with that observed in other studies described in the product labelling.

Dear Investigator letter distributed in November 2014


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Safety Issue


Notification of TSI

US

On 29 May 2015, the US FDA issued an official communication to Amgen Inc. of a “Notification of TSI” for epoetin alfa (EPOGEN/PROCRIT) regarding increased tumour recurrence and impaired survival with epoetin alfa treatment of anaemia in women receiving chemotherapy for breast cancer (EPO-ANE-3010). The FDA created this new TSI on 26 May 2015 for epoetin alfa (EPOGEN/PROCRIT).

New TSI created by FDA on 26 May 2015

“Notification of TSI” issued on 29 May 2015.

Postauthorisation measures with ESAs

PRAC Assessment

EU

On 12 March 2015, the PRAC issued advice to the CHMP regarding postauthorisationmeasures with ESAs, based on the outcome of the statistical analysis of clinical trial data in CKD patients on dialysis and not on dialysis.

The PRAC recommendation, which was endorsed by the CHMP, indicated that no new efficacy or safety concerns were identified based on the data reviewed. A HGB target range below 12 g/dL remains adequate but treatment should be more individualised and the lowest effective dose should be used. Caution is warranted with regard to dose escalation in patients with poor initial response to therapy. Sections 4.2 and 4.4 of the SmPCwere updated accordingly, and results of the analysis were added to Section 5.1. Consideration was given to issue a DHPCletter but it was decided to use other means of communication to ensure the targeted audience was made aware of the key messages. These means included publication of a key message on the EMA website and the possibility to communicate via EMA links to health care professionals.

PRAC adoption: 12 March 2015


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Safety Issue


Dear Healthcare Provider Communication

Global

In August 2017, the MAH distributed a DHPCletter to investigators to inform them of the postmarketing spontaneous reports of SCARs, including Stevens-Johnson syndrome and TEN (which can be life-threatening or fatal), which have been reported in association with epoetin treatment.

Severe cutaneous adverse reactions are considered to be a class effect of all epoetins. The reactions have been more severe with long-acting epoetins. The frequency of these severe cutaneous reactions could not be calculated but they occur very rarely.

If the patient has developed severe cutaneous adverse reactions (such as Stevens-Johnson syndrome or TEN, which are considered to be related to the use of an epoetin), the patient must never be given an epoetin again.

DHPC distributed in August 2017.


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Safety Issue


PRAC Assessment

EU

On 14 April 2016, a request by PRAC to update the RMP with 2 important identified risks, hypersensitivity reactions (including anaphylactic reactions) and seizures was made based on assessment of the PBRER. On 18 September 2017, in a subsequent RMS Day 40 Preliminary Variation Assessment Report and a teleconference between ANSM and the MAH (on 11 December 2017) a request to update the important identified risk of “hypertension” to “hypertension/hypertensive crisis” was made.

Note: Considering the new definition provided by the GVP module V rev 2, the RMS reconsidered the above request and requested the MAH to no longer consider “hypersensitivity/anaphylaxis” and “seizures” as important identified risks for inclusion in the EU RMP on 22nd May 2018. These two risks do not indeed meet the revised criteria for “important identified risks” to be included in the EU RMP as they are well characterized and described in the SmPC, and are not subject to additional pharmacovigilance or risk minimization activities.

Epoetin alfa should be used with caution in patients with epilepsy, history of seizures, or medical conditions associated with a predisposition to seizure activity, such as CNS infections and brain metastases. Hypertensive crisis with encephalopathy and seizures, requiring the immediate attention of a physician and intensive medical care, have occurred also during epoetin alfa treatment in patients with previously normal or low blood pressure. The occurrence of seizures during epoetin alfa treatment are uncommon.

Hypersensitivity reactions, including cases of rash (including urticaria), anaphylactic reactions, and angioneurotic oedema have been reported during epoetin alfa treatment and are uncommon.

PRAC adoption: 14 April 2016

Ab=antibody; ANSM=L'Agence Nationale de Sécurité du Médicament et des Produits de Santé; CCDS=Company Core Data Sheet; CHMP=Committee on Human Medicinal Products; CNS=central nervous system; CRF=chronic renal failure; DHPC=Dear Healthcare Provider Communication; EMA=European Medicines Agency; EMEA=European Medicines Evaluation Agency; ESA=erythropoiesis-stimulating agent; EU=European Union; FDA=Food and Drug Administration; HGB=haemoglobin; HSA=Health Sciences Authority (Singapore); IU=international units; MAH=marketing authorisation holder; PRAC=Pharmacovigilance Risk Assessment Committee; PRCA=pure red cell aplasia; RMP=risk management plan; RMS=risk management system; SC=subcutaneous; SCARs=severe cutaneous adverse reactions; SmPC=Summary of Product Characteristics; TEN=toxic epidermal necrolysis; TSI=Tracked Safety Issue;TVE=thrombotic vascular event; US=United States; USR=urgent safety restriction


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SV.2. Nonstudy Postauthorisation Exposure

SV.2.1. Method used to Calculate Exposure

The postmarketing exposure for epoetin alfa was estimated for distinct populations with the

following indications:

Chronic renal failure requiring dialysis

Chronic renal failure not yet requiring dialysis (predialysis)

Cancer

Surgery

Human immunodeficiency virus infection2

Market research data are not available for the ABD or MDS indication.

Estimates of the number of patients and PY of exposure were obtained for each country by year

using data from marketing surveys, patient registries, payer databases, and sales data as

available. The route of administration (SC versus IV) was also estimated using these same

surveys, as available, in specific countries for patients with CRF receiving dialysis and

predialysis.

SV.2.2. Exposure

The cumulative epoetin alfa postmarketing exposure from first product launch in 1989 through

31 August 2017 is person-years (PY) (data on postmarketing exposure in

the ABD indication are not available). The following tables show worldwide EPREX postauthorisation exposures by year and indication and EPREX postauthorisation exposures by

year and route of administration in patients with CRF (data available through August 2017).

2 While the HIV indication is not approved in the European Union, these exposure data have been included for completeness in this section.


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Worldwide Epoetin Alfa Postmarketing Exposures by Time Period and Indication in Person-Years (Cumulative to 31 August 2017)

Indication1989-2002

2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 20162017 YTD

Cumulative Totale

Dialysisa 1,711,101

162,929

163,815

159,271

157,496

162,600

166,124

162,597

154,215

148,913

147,957

136,897

134,199

120,281

118,343

73,130

Nephrology [pre-dialysis]

179,476 10,159 8,439 9,870 32,953 32,795 32,657 32,669 30,527 29,432 28,864 27,483 26,949 25,486 25,477 15,596

Cancerb

94,798 26,026 26,009 26,241 25,675 27,067 26,873 26,681 25,992 25,486 24,466 22,805 21,637 19,261 17,518 10,376

Surgeryc

5,147 2,919 3,320 4,177 3,136 3,293 2,920 2,768 2,509 2,393 2,197 1,992 1,939 1,699 1,517 873

HIV 1,420 4 6 80 0 0 0 0 0 0 0 0 0 0 0 0

Totald 1,991,942

202,038

201,590

199,640

219,260

225,755

228,573

224,715

213,243

206,225

203,484

189,177

184,724

166,727

162,855

99,976

Key: HIV=Human immunodeficiency virus; ICU=Intensive Care Unit; YTD=Year to Datea: Nephrology indication assumes a 52-week treatment course such that the number of patients is equal numerically to the number of person-years.b: The assumed duration of treatment for patients with cancer varied by time period within a range of 9 to 13 weeks.c: The assumed duration of treatment is a 4-week course.d: Estimates for non-approved indications Hepatitis C and ICU/Critical care are negligible and not included in this table.e: Figures are presented to the nearest patient-year for each product by time period and indication. If these figures are added up, minor rounding may occur with cumulative totals

which were calculated using raw data estimates for exposure.

Worldwide Postmarketing Exposure by Year and Route of Epoetin Alfa Administration Among Patients With Chronic Renal Failure

1989-2002

2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 20162017 YTD

Cumulative Total

Renal Dialysis

IV Exposure (person-years)

57,798 134,396

142,685

132,572

113,589

118,860

118,636

115,441

109,870

106,478

104,820

96,598

94,315

82,720

81,361

50,435

1,654,799

SC Exposure (person-years)

132,772 28,533 21,130 26,699 43,907 43,740 47,488 47,156 44,345 42,435 43,137 40,300

39,884

37,561

36,981

22,696

695,505

% IV Exposure 30% 82% 87% 83% 72% 73% 71% 71% 71% 72% 71% 71% 70% 69% 69% 69% 70%

% SC Exposure 70% 18% 13% 17% 28% 27% 29% 29% 29% 28% 29% 29% 30% 31% 31% 31% 30%

Pre-Dialysis Renal Disease

IV Exposure (person-years)

114 782 855 551 1,037 943 637 527 448 415 383 298 289 257 294 184 7,990

SC Exposure (person-years)

43,033 9,377 7,584 9,320 31,916 31,852 32,019 32,142 30,080 29,017 28,481 27,185

26,660

25,228

25,183

15,412

402,712

% IV Exposure 0% 8% 10% 6% 3% 3% 2% 2% 1% 1% 1% 1% 1% 1% 1% 1% 2%

% SC Exposure 100% 92% 90% 94% 97% 97% 98% 98% 99% 99% 99% 99% 99% 99% 99% 99% 98%

Key: IV=intravenous; SC=subcutaneous; YTD=Year to Date.Note: Data through 31 August 2017.


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Additional Stratifications for Epoetin Alfa

Patient exposure was estimated by calculation from Intercontinental Medical Statistics

Multinational Integrated Data Analysis System (IMS MIDAS) sales data. Estimates of

exposure are based upon finished product. Data from IMS MIDAS are available quarterly and

prorated as appropriate to fit the time period of interest. Additional stratifications are provided

using Intercontinental Medical Statistics (IMS) Health data where possible and appropriate.

Market research sources for nonstudy exposure data are unavailable for breakdowns such as:

usage in pregnant or breastfeeding women, usage in hepatic impairment population, usage in

renal impairment population.

Exposure by Age and Gender Presented as a Percentage of Prescription Sales

Prescription (Rx) sales stratified by age and gender from IMS MIDAS and are presented below

(as a percentage of total Rxs) (see the following tables). IMS Health retains age and gender data

for only 3 years, so these tabulations are not cumulative.

Further splits such as gender within age group are not provided since it is not appropriate to

stratify to this level of detail based on Rx information available from IMS for these

subcategories. Prescription units are reported as absolute values.

Postmarketing (Nonstudy) Epoetin Alfa Exposure by Age Group in the European Union (01 April 2014 to 31 March 2017)

EUb

Age Groups (Years)a

(635,447 Rxc)

0-17 0.17%18-35 2.10%36-64 13.69%65+ 84.04%

Key: EU=European Uniona: Regional Rx data by age are only available for the last 3 years ending March 2017.b: Data stratified by age are only available in the EU for the following G5 countries: France, Germany, Italy, Spain and United

Kingdom.c: Rx=Prescriptions in (absolute values), includes retail channels.

Postmarketing (Nonstudy) Epoetin Alfa Exposure by Age Group Outside the European Union (01 April 2014 to 31 March 2017)

Non-EUb

Age Groups (Years)a

(2,102,643 Rxc)

0-17 4.05%18-35 1.38%36-64 22.21%65+ 70.94%

Age Unspecified 1.42%Key: EU=European Uniona: Regional Rx data by age are only available for the last 3 years ending March 2017.b: Data stratified by age are only available in the EU for the following countries: Canada and the United States.c: Rx=Prescriptions in (absolute values), includes retail channels.


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Postmarketing (Nonstudy) Epoetin Alfa Exposure by Gender (01 April 2014 to 31 March 2017)

Region Femalesa

Malesa

Patient Gender Unidentifieda

Canada (64,790 Rxb) 61.04% 38.96% 0.00%

France (8,833 Rxb) 49.52% 50.48% 0.00%

Germany (15,923 Rxb) 38.65% 61.35% 0.00%

Italy (493,935 Rxb) 56.09% 43.91% 0.00%

Spain (112,817 Rxb) 44.99% 55.01% 0.00%

United Kingdom (3,939 Rxb) 89.44% 10.56% 0.00%

United States (2,037,853 Rxb) 53.91% 44.50% 1.59%

a: Regional Rx data by gender are only available for the last 3 years ending March 2017. Data is only available for France, Germany, Italy, Spain, United Kingdom, United States, and Canada.

b: Rx=Prescriptions in (absolute values), includes retail channels.

SV.3. Postauthorisation Use in Populations Not Studied in Clinical Trials

Market research sources for nonstudy postmarketing exposure data were unavailable for

breakdowns such as: usage in pregnant or breastfeeding women, usage in the hepatic impairment

population, or usage in the renal impairment population.

SV.4. Postauthorisation Off-label Use

Non-EU approved uses outside the setting of Company-sponsored/-supported clinical trials

includes treatment of anaemia in adult human immunodeficiency virus (HIV)-infected patients

being treated with zidovudine having endogenous erythropoietin levels ≤500 mU/mL (approved

in some non-EU jurisdictions) and settings in which an increase in red cell mass is desired, such

as MDS, anaemia of acute and chronic disease, anaemia associated with ribavirin and interferon

treatment for hepatitis C, and haemoglobinopathies. Exposure information in non-approved uses

is limited.

SV.5. Epidemiologic Study Exposure

Details regarding epidemiologic study exposure are provided in the following table. Additional

information regarding the Pharmacoepidemiology Registry EPO-ANE-4014 Prospective

Immunogenicity Surveillance (PRIMS) registry is provided in Annex 9. An overview of results

for Trials EPO-IMU-401, EPO-IMU-402, and EPO-ANE-4014 is provided in Annex 4.

Additional information regarding Trial EPOANE4076 is provided in Annex 9.


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Study titleStudy type Objectives

Population studied(data source and country)

Duration(study period)

Number of persons (in each group or of cases and controls) and person time(if appropriate) Comment

EPO-IMU-401/402Prospective, observational cohort

To prospectively monitor the incidence of PRCA among patients with chronic renal disease who are receiving treatment with epoetin alfa or other erythropoietins.

Patients with CRF who were receiving a Company-marketed ESA; later expanded to include all ESAs. Conducted in Australia, Canada,France, and Germany.

Patients were followed for no less than 1 year after enrolmentand followed up for 12 months after the last dose.

9,791 Study informationin Annex 4

EPO-ANE-4014non-interventional immunogenicity surveillance registry, prospective cohort design with enrolmentof parallel groups

Estimate IRrate of EPO Ab-mediated PRCA SC exposure to PS-80 formulation of EPREX compared with other currently marketed ESA.

Patients were to have documented CRF (any stage) and be receiving or about to receive SC (within 1 month of the date of enrolment) a marketed ESA.Conducted in 16 EU countries plus Norway,Switzerland, and Australia.

Patients who received SC ESAs were followed up quarterly for 3 years.

15,333 patientswere enroled: 5,948 patients received EPREX as initial study treatment, 5,974 Aranesp, 3,382 NeoRecormon.29 patients did not have treatment data available.9,602 patientscompleted the registry: 3,753 EPREX, 3,772 Aranesp, 2,077 NeoRecormon.

Study synopsis in Annex 9


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Study titleStudy type Objectives

Population studied(data source and country)

Duration(study period)

Number of persons (in each group or of cases and controls) and person time(if appropriate) Comment

EPOANE4076A prospective, immunogenicity surveillance registry of ESAswith SCexposure in Thailand

Estimate the incidence of anti-humanerythropoiesis and anti-erythropoietin PRCA in patients using any ESA by the SC route.

Patients with CRF receiving ESAs. Conducted in Thailand.

Patients wereobserved for the development of immunogenicity and PRCA for up to 3 years.

4,018 patients were enroled.

Results indicatedthat 9 cases of erythropoietin Ab-mediated PRCA were reported. All 9 cases received biocopy r-HuEPO products. The IR of erythropoietin Ab-mediated PRCA cases regardless of specific brand was 1.7 cases per 1,000 PY (95% CI: 0.7812, 3.24). The mean duration of ESA exposure in the 9 erythropoietin Ab-mediated PRCA cases was 13.6 months. Bone marrow biopsies were performed and confirmed PRCA in all cases.

Ab=antibody; CI=confidence interval; CRF=chronic renal failure; ESA=erythropoiesis-stimulating agent; EU=European Union; IR=incidence rate; PRCA=pure red cell aplasia; PS-80=polysorbate 80; PY=person-years; r-HuEPO=recombinant human erythropoietin; SC=subcutaneous


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Module SVI: Additional EU Requirements for the Safety Specification











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SVI.1. Potential for Harm From Overdose

The therapeutic margin of epoetin alfa is very wide. Overdosage of epoetin alfa may produce

effects that are extensions of the pharmacologic effects of the hormone. Phlebotomy may be

performed if excessively high HGB levels occur. Additional supportive care should be provided

as necessary. There is no risk for intentional overdose.

SVI.2. Potential for Transmission of Infectious Agents

Good Manufacturing Practices are routinely followed by the MAH and EPREX is produced

under Good Manufacturing Practices. No potential for transmission of infectious agents with the

use of EPREX has been identified. The MAH performs routine pharmacovigilance activities. If

transmission of an infectious agent via EPREX is suspected, appropriate investigations will be

conducted. In April 1998, upon request from the EU health authorities, the MAH removed

human serum albumin from the formulation and replaced it with polysorbate-80 (PS-80) to

eliminate potential risks of contamination by viruses or prions.

SVI.3. Potential for Misuse for Illegal Purposes

Erythropoiesis-stimulating agents have the potential for misuse by endurance athletes to increase

HGB levels to enhance aerobic power and performance. The Company’s Global Medical Safety

database is searched for medically confirmed cases received during each Periodic Benefit-Risk

Evaluation Report (PBRER)/Periodic Safety Update Report (PSUR) reporting period that meet

PSUR reporting criteria and are coded to Medical Dictionary for Regulatory Activities

(MedDRA) preferred terms that may involve drug abuse/misuse. No cases reporting drug

abuse/misuse for illegal purposes have been received to date. The potential for misuse for illegal

purposes is low.

SVI.4. Potential for Medication Errors

Medication errors have been associated with the use of EPREX. These medication errors, such as

inappropriate storage (storage at ambient temperature), incorrect dosage (either dose or

frequency of administration), or use of expired product, have not resulted in clinically serious

sequelae.

SVI.4.1. Description of Medication Errors During the Clinical Trial Programme

The clinical trial programme for EPREX spans back to the 1980s and in many of the older trials,

medication errors were not captured as such in the case report forms. Therefore, information

about medication errors and corresponding preferred terms in the entire clinical database is very

limited. Data are available from 3 large, randomised, controlled trials in which these data were

collected (CRF indication: EPO-AKD-3001 and EPO-AKD-3002; cancer indication:

EPO-ANE-4008). These trials were reviewed for medication errors involving EPREX and the

data are summarised in the following table. Categories of preferred terms evaluated included the

administration of incorrect medication, incorrect dosing, incorrect route of administration, or

incorrect patient administered dose.


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Description of Medication Errors During the Clinical Trial Programme(s)

Product Name(s)Description of error

Number of occurrences Analysis of cause Steps taken to prevent Comment

Inappropriate schedule of drug administration

1 Dose of EPREX given less than 24 hours apart

Trial monitor reviewed correct scheduling of drug administration

The trial is closed and no further action is needed

Incorrect dose adjustment

27 Reports of EPREX doses not being increased or decreased per the protocol

Trial monitor reviewed correct dosing adjustments


Incorrect storage of drug

19 Reports included EPREXtemperature excursions. Many reports lacked detailed information and could not be further evaluated

Trial monitor reviewed the need for temperature control


Dosing administration error

28 Reports of doses being prescribed and the HCP not giving the prescribed dose. Also reports of dosing of nonstudydrug on non-dosing week

Trial monitor reviewed dosing and protocol requirements with investigator


Wrong data provided for dosing

2 Patients weights were incorrectly recorded leading to incorrect dose administered

Trial monitor reviewed need for appropriate weights and calculation of dosing based off of the weight


HCP=health care provider; MAH=Market Authorisation Holder

SVI.4.2. Preventive Measures for the Final Product(s) Being Marketed

To prevent medication errors, accidental exposure to the product, and the incorrect route of

administration, Section 4.2 of the SmPC clearly states how the drug should be administered. To

prevent the use of expired or poor quality drug administration, Section 6.3 of the SmPC clearly

states the shelf life of the product and Section 6.4 of the SmPC clearly states how the product

should be stored. Section 6.6 of the SmPC describes the special precautions for handling and

disposal as well as a statement not to use the product and discard it if the seal is broken. To

prevent drug label or name confusion, the SmPC clearly states “epoetin alfa” and provides

guidance on appropriate units of drug. Anti-counterfeiting features on the EPREX packaging


133

include 1) syringe label contains a field with a Janssen varnish spot, and 2) folding box contains

a hidden image on one flap.

SVI.4.3. Effect of Device Failure

In August 2013, ANSM recommended that, based on a high number of customer complaints

associated with the use of the PROTECS safety device in Canada (since its launch in

December 2007), the MAH should clarify if similar product complaints related to the protective

needle-guard system had occurred in Europe. The Company identified that the highest category

of EPREX customer complaints was related to “needle safety shield issues/device activation”. In

this situation, the needle safety device can be accidentally activated due to human error while

removing the syringe from the blister prior to administration.

In Europe, between January 2008 and October 2013, syringes had been shipped and in that time, there were 891 reports of “device and delivery system issues”. It

should be noted that the number of complaints have declined each year since 2008 when the

PROTECS device was first introduced in Europe. The Company considers the initial increase in

complaint rates to be associated with customers being unfamiliar with the PROTECS device and

not with a failure of the device itself. However, to aid patients with the appropriate use of the

PROTECS device, the Company took a proactive measure to update the Package Leaflet to

provide more detailed instructions and an updated diagram of the PROTECS system to ensure

patient safety. The Company will continue to monitor device complaints and report in the

PBRER/PSUR.SVI.4.4. Reports of Medication Errors with the Marketed Product(s)

Description of ErrorNumber of Occurrences Analysis of Cause

Steps Taken to Prevent Comment

Accidental ExposureAccidental exposure to product

15 Accidental exposure (including ingestion, skin, and/or eye exposure) to patient/HCP or accidental needle stick to the HCP due to leaky syringe, spring/plunger not working, needle-guard malfunction, or bent needle.

Section 4.2 of the SmPC and the Package Leaflet provide information on how the drug should be administered.

No serious events reported.

Drug Administration ErrorPoor quality drug administered

91 The patients received epoetin alfa that was stored at room temperature, frozen, or expired.

Section 6.4 of the SmPC states how the product is to be stored.

Serious unlisted eventb: Uterine cancer (1). The MAH will continue to monitor reports of medication error.


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Expired productadministered

40 Expired drug was administered by either the HCP or the patient

Section 6.3 of the SmPC states the shelf life of the product.

No serious events reported.

Drug administration error

31 Described various errors: administration to the wrong patient, receiving drug stored at room temperature, given via IM route, “partial amount” administered, and cold drug or empty syringe

Section 4.2 of the SmPC clearly defines how thedose is to be taken.

Serious unlisted eventsb: Death (1), Hyperkalaemia (1), and Plasma cell myeloma (1); the MAH will continue to monitor reports of medication error

Incorrect route of drug administration

20 Epoetin alfa was administered via IM, IV (instead of SC), inhalation, oral, “intra-dermal”, or through catheter route


Serious unlisted eventb:

Hypertension (1). The MAH will continue to monitor reports of medication error.

Treatment noncompliance

4 Reported treatment noncompliance due to fear of needles, patient refusal, or unspecified reason.

Section 4.2 of the SmPC clearly defines how the dose is to be taken.

No serious unlisted events reported.b

Drug administered to patient of inappropriate age

2 Epoetin alfa prescribed to female patients aged 1-month-old and 6-months-old, respectively

Sections 4.1 and 4.2 of the SmPC clearly state indication and dose to be taken, respectively.

No serious unlisted events reportedb

Wrong drug administered

3 Involved administration of epoetin alfa instead of epoetin beta or an unspecified drug

The SmPC clearly states the correct name of drug.

No serious events reported

Drug Dispensing/ Prescribing ErrorDrug prescribing error

55 Prescribed for unapproved indication or patient population (paediatric), orincorrect dose/route/frequency

Sections 4.1 and 4.2 of the SmPC clearly statesindication and dose to be taken, respectively.

No serious events reported

Drug dispensing error

16 Involved dispensing of incorrect dose, dose strength 10 times the prescribed dose,expired drug, or




135



dispensing of wrong drug.

Inappropriate Schedule of Drug AdministrationDrug dose omission 62 Missed doses due to

syringe-/needle-guard defect/malfunction, incorrectly stored drug, wrong dose dispensed, or forgotten

Section 4.2 of the SmPC clearly defines how thedose is to be taken and Section 6.4 of the SmPC stateshow the product is to be stored.

No serious unlisted events reported.b

Inappropriate schedule of drug administration

41 Administration of epoetin alfa at shorter or longer dosing intervals than prescribed


Serious unlisted eventsa: Dizziness (1), Malaise (1), Chest discomfort (1), Extramedullary haematopoiesis (1); the MAH will continue to monitor the inappropriate schedule of drug administration

Incorrect Dose AdministeredIncorrect dose administered

46 Involved receiving less or more than the prescribed/recommended dose


Serious unlisted events: Spinal cord compression (1), Extramedullary haemopoiesis (1), Sepsis (1), and Aplasia pure red cell (1); the MAH will continue to monitor the incorrect dose administered

Incorrect Product StorageIncorrect product storage

135 Epoetin alfa was stored at room temperature, in the freezer, or was refrigerated at temperature higher/lower than the label recommended

Section 6.4 of the SmPC states how the product is to be stored.


Intercepted drug administration error

1 Described a HCPwho discovered the wrong dose was dispensed to the patient and did not administer the drug


No serious adverse events reported


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Product Label/Name ConfusionProduct label confusion

3 Described prefilledsyringes labelled 1,000 IU/0.5 mL which led to unspecified “mistakes”, pharmacist ordered epoetin alfa 40,000 IU prefilled syringe 0.75 mL instead of 1.0 mL, and patient did not know how to handle the PROTECS needle

The SmPC provides clear guidance on appropriate units of drug.

No serious adverse event reported

Product name confusion

1 Epoetin alfa was dispensed instead of Enbrel® (etanercept)

The SmPC clearly states epoetin alfa.

No serious adverse events reported

Product TamperingProduct tampering 1 Epoetin alfa prefilled

syringe was not sealed with plastic wrap

Section 6.6 of the SmPC describes instructions for use, handling, and disposal.

No serious adverse event reported

UnderdoseUnderdose 35 Most of the cases

reported receiving partial dose as a result of syringe/needle issues, while some cases described dropping the syringe during administration, patient not obtaining enough drug, or patient not being aware of the dose increase


Serious unlisted events: Sepsis (1), Aplasia pure red cell (1); the MAH will continue to monitor reports of medication error.

Wrong Technique in Drug Usage ProcessWrong technique in drug usage process

13 Described various circumstances including wrong technique during injection, re-use of syringe, shaking of drug prior to administration, or injecting drug that

Section 4.2 of the SmPC clearly defines how thedose is to be taken and Sections 6.4 and 6.6 of the SmPC define how the product is to be stored.



137



was frozen or had air bubbles

Medication Error (Miscellaneous)Medication error 24 Involved various

errors that included dispensing the wrong needle guard for the dose, improper storage, HCP ordering the wrong strength concentration, receiving batch number that was not distributed in that country

Section 4.2 of the SmPC clearly defines how thedose is to be taken and Section 6.4 of the SmPC stateshow the product is to be stored.

Serious unlisted event: Blood pressure abnormal (1), Fall (1); the MAH will continue to monitor reports of medication error.

Circumstance or information capableof leading to medication error

1 Patient received drug from syringe with the PROTECS system

Section 4.2 of the SmPC clearly defines how the dose is to be taken.

No serious adverse events reported.

AE=adverse event; CCDS=Company Core Data Sheet; CT=computerised tomogram; HCP=health care provider; IM=intramuscular; IV=intravenous; MAH=marketing authorisation holder; MDS=myelodysplastic syndrome; MRI=magnetic resonance imaging; SC=subcutaneous; SmPC=Summary of Product Characteristics

a: Number of occurrences is derived from total reported counts for each individual MedDRA preferred term based on Global Medical Safety (GMS) Safety Data Extraction ticket number SDE002650 (dated 13 July 2015).

b: Serious unlisted events (based on the CCDS) were only included if they were temporally associated with medication error and/or an association with the medication error appeared to be plausible.

SVI.5. Potential for Off-label Use

The potential exists that EPREX will be prescribed in a manner that is not consistent with the

product label (eg, in patients with a different treatment indication, in a different patient

population, or in the administration of the product).

Based on the review of the safety data, there is the potential for EPREX to be used to treat

patients with other causes of anaemia and to be prescribed, administered, or used incorrectly.

The common off-label uses included the treatment of anaemia associated with haematologic

malignancy or anaemia induced by hepatitis C treatment. Approved indications for the product

are stated in the SmPC, as well as the dosage and administration recommendations.

SVI.6. Specific Paediatric Issues

SVI.6.1. Issues Identified in Paediatric Investigation Plans

There is no Paediatric Investigational Plan for EPREX.


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SVI.6.2. Potential for Paediatric Off-label Use

Section 4.1 of the SmPC states that EPREX is indicated for the treatment of symptomatic

anaemia associated with CRF in paediatric patients on haemodialysis. Exposure in non-approved

uses is limited.

SVI.7. Conclusions

There are no safety concerns identified from this module.


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Module SVII: Identified and Potential Risks











140

SVII.1. Newly Identified Safety Concerns (since this module was last submitted)

Hypertensive crisis has been added to the Important Identified Risk of Hypertension.

SVII.2. Recent Study Reports With Implications for Safety Concerns

Completed trials from the Postauthorisation Pharmacovigilance Plan are summarised in

Section III.5.2.

Trial EPO-ANE-3010 is a randomised, open-label, multicentre, Phase 3 international trial of

epoetin alfa plus best standard supportive care versus standard supportive care alone in anaemic

patients with metastatic breast cancer receiving standard chemotherapy. Patients were assessed

for tumour response during the open-label phase every 8 weeks for 1 year after randomisation or

until there was documented progressive disease. After 1 year in the absence of progressive

disease, patients were evaluated for tumour response every 12 weeks. Patients continued in the

open-label phase until progressive disease was documented or the patient died, even if the

patient’s chemotherapy was discontinued or changed. Following the documentation of

progressive disease, patients entered the long-term follow-up phase, during which time survival

status was checked every 3 months until the patient died/withdrew or the trial ended.

A clinical study report (CSR) for Trial EPO-ANE-3010 has been completed given that the

number of progression-free survival (PFS) events reached the target of 1,650 events for the

analysis of the primary endpoint. A final analysis for survival was performed after 1,650 patients

died. As of the clinical cutoff date of 07 July 2014 for the CSR, the median PFS per investigator

assessment of disease progression was 7.4 months in each arm (HR 1.09, 95% CI: 0.99, 1.20),

indicating that the study objective was not met. Median PFS with disease progression assessed

by the Independent Review Committee was 7.6 months in each arm (HR 1.03, 95% CI: 0.92,

1.15). At the time of the clinical cutoff date of 07 July 2014 for the CSR, 1,337 deaths were

reported. Median overall survival in the epoetin alfa plus standard-of-care group was

17.2 months compared with 17.4 months in the standard-of-care alone group (HR 1.06, 95%

CI: 0.95, 1.18).

SVII.3. Details of Important Identified and Potential Risks From Clinical Development and Postauthorisation Experience(including newly identified)

Important Identified Risks with the use of EPREX are:

Thrombotic vascular events

Pure red cell aplasia

Hypertension/Hypertensive crisis


141

Important Potential Risks with the use of EPREX are:

Disease progression

Survival impact

Congestive heart failure

Odds ratios and 95% CI for the risk of each adverse event in epoetin alfa-treated patients are also

presented in these tables for the randomised trials. A risk was considered statistically

significantly higher in the epoetin alfa-treated group than in the control group without epoetin

alfa, when the lower boundary of the 95% CI of the ORs was larger than 1.0 (ie, when the

95% CI did not include 1.0). Odds ratios are provided only for the analyses including trials with

a control group, as providing ORs for a mixture of trials with control and trials without control is

not appropriate and can lead to misinterpretation.

With clinical trial programme experience of over 25 years, data related to severity and outcomes

for nonserious adverse events were not collected for a majority of the epoetin alfa trials. The

legacy trials did not capture NCI-CTCAE (Common Terminology Criteria for Adverse Events)

(CTCAE), formerly called the Common Toxicity Criteria (CTC or NCI CTC) grading. The risk

tables present a combination for each risk of the severity grading of mild, moderate, or severe,

where applicable, and the toxicity grades (Grades 1 to 4), where applicable.

Therefore, due to the difference in reporting of toxicity grades versus non-toxicity severities, the

characterisation of severity and outcomes data are only provided for serious adverse events and a

total for all indications per risk is not provided.

The data below came from clinical trials that included both labelled (correction of anaemia) and

non-labelled (beyond correction of anaemia) dosage regimens. MedDRA Version 20.0

(the current version at the time of the database lock for this analysis) was used to classify the

clinical trials adverse event information that is summarised in this module.


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Important Identified Risks

Important Identified Risk - Thrombotic Vascular Events

Frequency (Odds Ratio, 95% Confidence Interval), SAE Outcomes, and Severity of Thromboembolic Vascular Events in Randomised Controlled Clinical Trials, Clinical Trials Without Control, and All Clinical Trials

INDICATION: CHRONIC RENAL FAILURE - DIALYSISEpoetin alfa (N=2046) Non-ESA control (N=46) Odds Ratio a (95% CI)

Randomised Controlled Trials b 97 46NAny Treatment-Emergent Event, n (%) 2 (2.06%) 0 (0.00%) N/AOutcome (Based on Serious AEs) 0 0Fatal 0 (0.00%) 0 (0.00%)Hospitalised 0 (0.00%) 0 (0.00%)Not Recovered 0 (0.00%) 0 (0.00%)Recovered 0 (0.00%) 0 (0.00%)N/A 0 (0.00%) 0 (0.00%)Severity, n (%)Mild 0 (0.00%) 0 (0.00%)Moderate 0 (0.00%) 0 (0.00%)Severe 1 (1.03%) 0 (0.00%)Unknown 1 (1.03%) 0 (0.00%)Missing 0 (0.00%) 0 (0.00%)

Trials without control c 1949 0NAny Treatment-Emergent Event, n (%) 255 (13.1%) 0 (0.00%) N/AOutcome (Based on Serious AEs) 154 0Fatal 3 (0.15%) 0 (0.00%)Hospitalised 0 (0.00%) 0 (0.00%)Not Recovered 19 (0.97%) 0 (0.00%)Recovered 131 (6.72%) 0 (0.00%)N/A 1 (0.05%) 0 (0.00%)Severity, n (%)Mild 51 (2.62%) 0 (0.00%)Moderate 75 (3.85%) 0 (0.00%)Severe 129 (6.62%) 0 (0.00%)Unknown 0 (0.00%) 0 (0.00%)Missing 0 (0.00%) 0 (0.00%)

Combined (All Trials) 2046 46NAny Treatment-Emergent Event, n (%) 257 (12.6%) 0 (0.00%)Outcome (Based on Serious AEs) 154 0Fatal 3 (0.15%) 0 (0.00%)Hospitalised 0 (0.00%) 0 (0.00%)Not Recovered 19 (0.93%) 0 (0.00%)Recovered 131 (6.40%) 0 (0.00%)N/A 1 (0.05%) 0 (0.00%)Severity, n (%)Mild 51 (2.49%) 0 (0.00%)Moderate 75 (3.67%) 0 (0.00%)Severe 130 (6.35%) 0 (0.00%)Unknown 1 (0.05%) 0 (0.00%)Missing 0 (0.00%) 0 (0.00%)AE=adverse event; CI=confidence interval; ESA=erythropoiesis-stimulating agent; N/n=number; N/A=not applicablea The stratified Mantel-Haenszel odds ratio (stratified by trial) was used.b Includes EP86-001 (CEO-C01), EP86-004c Includes EPO-CAN-1, EPO-CAN-13, EPO-INT-37, EPO-INT-68, EPO-INT-77, EPO-ITA-2, ZEO-107 (CCP107P108),

ZEO-121 (CC2574P121), ZEO-S01 (CCP102P103)Chronic Renal Failure – Dialysis Trials: EP86-001 (CEO-C01), EP86-004, EPO-CAN-1, EPO-CAN-13, EPO-INT-37, EPO-INT-68, EPO-INT-77, EPO-ITA-2, ZEO-107 (CCP107P108), ZEO-121 (CC2574P121), ZEO-S01 (CCP102P103)

[TAE01A.rtf] [JNJ-7472179\Z_RMP\RMP_2015\RE_RMP_2015_EU\tae01a.sas] 23APR2015, 14:01


143


INDICATION: CHRONIC RENAL FAILURE - PREDIALYSISEpoetin alfa (N=5610) Non-ESA control (N=325) Odds Ratio a (95% CI)

Randomised Controlled Trials b 464 325NAny Treatment-Emergent Event, n (%) 23 (4.96%) 8 (2.46%) 2.26 (0.98,5.24)Outcome (Based on Serious AEs) 13 3Fatal 1 (0.22%) 0 (0.00%)Hospitalised 0 (0.00%) 0 (0.00%)Not Recovered 2 (0.43%) 0 (0.00%)Recovered 10 (2.16%) 3 (0.92%)N/A 0 (0.00%) 0 (0.00%)Severity, n (%)Mild 5 (1.08%) 3 (0.92%)Moderate 8 (1.72%) 2 (0.62%)Severe 10 (2.16%) 2 (0.62%)Unknown 0 (0.00%) 1 (0.31%)Missing 0 (0.00%) 0 (0.00%)


Combined (All Trials) 5610 325NAny Treatment-Emergent Event, n (%) 290 (5.17%) 8 (2.46%)Outcome (Based on Serious AEs) 207 3Fatal 33 (0.59%) 0 (0.00%)Hospitalised 0 (0.00%) 0 (0.00%)Not Recovered 9 (0.16%) 0 (0.00%)Recovered 131 (2.34%) 3 (0.92%)N/A 34 (0.61%) 0 (0.00%)Severity, n (%)Mild 46 (0.82%) 3 (0.92%)Moderate 78 (1.39%) 2 (0.62%)Severe 148 (2.64%) 2 (0.62%)Unknown 18 (0.32%) 1 (0.31%)Missing 0 (0.00%) 0 (0.00%)

AE=adverse event; CI=confidence interval; ESA=erythropoiesis-stimulating agent; N/n=number; N/A=not applicablea The stratified Mantel-Haenszel odds ratio (stratified by trial) was used.b Includes EPO-AUS-14, EPO-CAN-10, EPO-ITA-7, EPOCKD2002, G86-011, H87-054c Includes CHOIR (PR00-06014), EPOCKD2001, EPO-AKD-3001, EPO-AKD-3002, EPO-INT-14, G86-053, G86-125,

H87-055, N93-063, POWER (PR00-06009), PROMPT (PR01-06021), Q2W INITIATION (PR03-06001), EPO-NED-15

Chronic Renal Failure – Predialysis Trials: CHOIR (PR00-06014), EPOCKD2001, EPOCKD2002, EPO-AKD-3001, EPO-AKD-3002, EPO-AUS-14, EPO-CAN-10, EPO-INT-14, EPO-ITA-7, G86-011, G86-053, G86-125, H87-054, H87-055, N93-063, POWER (PR00-06009), PROMPT (PR01-06021), Q2W INITIATION (PR03-06001), EPO-NED-15

[TAE01B.rtf] [JNJ-7472179\Z_RMP\RMP_2015\RE_RMP_2015_EU\tae01b.sas] 23APR2015, 14:01


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INDICATION: ONCOLOGYEpoetin alfa (N=5827) Non-ESA control (N=4719) Odds Ratio a (95% CI)

Randomised Controlled Trials b 5323 4719NAny Treatment-Emergent Event, n (%) 358 (6.73%) 182 (3.86%) 1.88 (1.56,2.27)Outcome (Based on Serious AEs) 97 41Fatal 12 (0.23%) 5 (0.11%)Hospitalised 0 (0.00%) 0 (0.00%)Not Recovered 35 (0.66%) 10 (0.21%)Recovered 45 (0.85%) 19 (0.40%)N/A 5 (0.09%) 7 (0.15%)Severity, n (%)Grade=1 39 (0.73%) 25 (0.53%)Grade=2 102 (1.92%) 55 (1.17%)Grade=3 201 (3.78%) 90 (1.91%)Grade>=4 5 (0.09%) 5 (0.11%)Unknown 11 (0.21%) 7 (0.15%)

Trials without control c 504 0NAny Treatment-Emergent Event, n (%) 28 (5.56%) 0 (0.00%) N/AOutcome (Based on Serious AEs) 24 0Fatal 1 (0.20%) 0 (0.00%)Hospitalised 0 (0.00%) 0 (0.00%)Not Recovered 9 (1.79%) 0 (0.00%)Recovered 14 (2.78%) 0 (0.00%)N/A 0 (0.00%) 0 (0.00%)Severity, n (%)Grade=1 5 (0.99%) 0 (0.00%)Grade=2 14 (2.78%) 0 (0.00%)Grade=3 8 (1.59%) 0 (0.00%)Grade>=4 1 (0.20%) 0 (0.00%)Unknown 0 (0.00%) 0 (0.00%)

Combined (All Trials) 5827 4719NAny Treatment-Emergent Event, n (%) 386 (6.62%) 182 (3.86%)Outcome (Based on Serious AEs) 121 41Fatal 13 (0.22%) 5 (0.11%)Hospitalised 0 (0.00%) 0 (0.00%)Not Recovered 44 (0.76%) 10 (0.21%)Recovered 59 (1.01%) 19 (0.40%)N/A 5 (0.09%) 7 (0.15%)Severity, n (%)Grade=1 44 (0.76%) 25 (0.53%)Grade=2 116 (1.99%) 55 (1.17%)Grade=3 209 (3.59%) 90 (1.91%)Grade>=4 6 (0.10%) 5 (0.11%)Unknown 11 (0.19%) 7 (0.15%)


145

AE=adverse event; CI=confidence interval; ESA=erythropoiesis-stimulating agent; N/n=number; N/A=not applicablea The stratified Mantel-Haenszel odds ratio (stratified by trial) was used.b Includes CISPLATIN (I88-036, OEO-U24 and OEO-U25), NON-CHEMOTHERAPY (H87-032, OEO-U20 and

OEOU21), NON-CISPLATIN (I88-037, OEO-U22 and OEO-U23), AGO/NOGGO (EPO-GER-8), EP92-002, EPO-CAN-15, EPO-CAN-17, EPO-CAN-20, EPO-CAN-203, EPO-CAN-303, EPO-GBR-4, EPO-GBR-7, EPO-GER-20, EPO-GER-22, EPO-GOG-191, EPO-INT-1 (2574-P-416), EPO-INT-10 (EPO-C111-457), EPO-INT-2 (CC2574-P-467), EPO-INT-3 (2574-P-034), EPO-INT-45, EPO-INT-47, EPO-INT-49, EPO-INT-50, EPO-INT-51 (EPO-CA-484), EPO-INT-76 (EPO-CA-489), EPO-J89-040 (J89-040), EPO-N93-004 (N93-004), EPO-P-169 (2574-P-169), EPO-P-174(CC2574-P-174), MOEBUS, OBE/EPO-INT-03, PR00-03-006, PR00-27-005, PR98-27-008, PR99-11-034/044, PRI/EPO-NED-17, RTOG/PR99-03-046 (PR99-03-046), EPO-CAN-29, EPO-ANE-3010

c Includes EPO-ANE-4008

Oncology Trials: CISPLATIN (I88-036, OEO-U24 and OEO-U25), NON-CHEMOTHERAPY (H87-032, OEO-U20 and OEOU21), NON-CISPLATIN (I88-037, OEO-U22 and OEO-U23), AGO/NOGGO (EPO-GER-8), EP92-002, EPO-ANE-4008, EPO-CAN-15, EPO-CAN-17, EPO-CAN-20, EPO-CAN-203, EPO-CAN-303, EPO-GBR-4, EPO-GBR-7, EPO-GER-20, EPO-GER-22, EPO-GOG-191, EPO-INT-1 (2574-P-416), EPO-INT-10 (EPO-C111-457), EPO-INT-2 (CC2574-P-467), EPO-INT-3 (2574-P-034), EPO-INT-45, EPO-INT-47, EPO-INT-49, EPO-INT-50, EPO-INT-51 (EPO-CA-484), EPO-INT-76 (EPO-CA-489), EPO-J89-040 (J89-040), EPO-N93-004 (N93-004), EPO-P-169 (2574-P-169), EPO-P-174 (CC2574-P-174), MOEBUS, OBE/EPO-INT-03, PR00-03-006, PR00-27-005, PR98-27-008, PR99-11-034/044, PRI/EPO-NED-17, RTOG/PR99-03-046 (PR99-03-046), EPO-CAN-29, EPO-ANE-3010

[TAE01C.rtf] [JNJ-7472179\Z_RMP\RMP_2015\RE_RMP_2015_EU\tae01c.sas] 05NOV2015, 11:05


INDICATION:AUTOLOGOUS BLOOD DONATIONEpoetin alfa (N=402) Non-ESA control (N=242) Odds Ratio a (95% CI)

Randomised Controlled Trials b 402 242NAny Treatment-Emergent Event, n (%) 10 (2.49%) 7 (2.89%) 1.00 (0.38,2.61)Outcome (Based on Serious AEs) N/A N/ASeverity, n (%)Mild 0 (0.00%) 2 (0.83%)Moderate 6 (1.49%) 3 (1.24%)Severe 4 (1.00%) 1 (0.41%)Missing 0 (0.00%) 1 (0.41%)

Combined (All Trials) 402 242NAny Treatment-Emergent Event, n (%) 10 (2.49%) 7 (2.89%)Outcome (Based on Serious AEs) N/A N/ASeverity, n (%)Mild 0 (0.00%) 2 (0.83%)Moderate 6 (1.49%) 3 (1.24%)Severe 4 (1.00%) 1 (0.41%)Missing 0 (0.00%) 1 (0.41%)

AE=adverse event; ABD=autologous blood donation; CI=confidence interval; ESA=erythropoiesis-stimulating agent; N/n=number; N/A=not applicablea The stratified Mantel-Haenszel odds ratio (stratified by trial) was used.b Includes CC 2574-P-159, CC 2574-P-165, CC 2574-P-166, H87-017, H87-036, I88-027, I88-058

ABD Trials: CC 2574-P-159, CC 2574-P-165, CC 2574-P-166, H87-017, H87-036, I88-027, I88-058

[TAE01D.rtf] [JNJ-7472179\Z_RMP\RMP_2015\RE_RMP_2015_EU\tae01d.sas] 23APR2015, 14:01


146


INDICATION:SURGERYEpoetin alfa (N=1352) Non-ESA control (N=922) Odds Ratio a (95% CI)




AE=adverse event; CI=confidence interval; ESA=erythropoiesis-stimulating agent; N/n=number; N/A=not applicablea The stratified Mantel-Haenszel odds ratio (stratified by trial) was used.b Includes EPO-APO2-474, EPO-INT-34 (EPO-AP02-478), CEO-C04, H87-083, J89-001, M92-011, PR97-19-002 (spine)c Includes N93-057

Surgery Trials: EPO-APO2-474, EPO-INT-34 (EPO-AP02-478), CEO-C04, H87-083, J89-001, M92-011, N93-057, PR97-19-002 (spine)

[TAE01E.rtf] [JNJ-7472179\Z_RMP\RMP_2015\RE_RMP_2015_EU\tae01e.sas] 28OCT2015, 09:37


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INDICATION: MDS Epoetin alfa (N=102) Non-ESA control (N=53) Odds Ratio a (95% CI)

Randomised Controlled Trials b 102 53NAny Treatment-Emergent Event, n (%) 2 (1.96%) 0 (0.00%) N/AOutcome (Based on Serious AEs) 1 0Fatal 0 (0.00%) 0 (0.00%)Hospitalised 0 (0.00%) 0 (0.00%)Not Recovered 0 (0.00%) 0 (0.00%)Recovered 1 (0.98%) 0 (0.00%)N/A 0 (0.00%) 0 (0.00%)Severity, n (%)Grade=1 1 (0.98%) 0 (0.00%)Grade=2 0 (0.00%) 0 (0.00%)Grade=3 1 (0.98%) 0 (0.00%)Grade>=4 0 (0.00%) 0 (0.00%)Unknown 0 (0.00%) 0 (0.00%)


AE=adverse event; CI=confidence interval; ESA=erythropoiesis-stimulating agent; MDS=myelodysplastic syndrome; N/n=number; N/A=not applicablea The stratified Mantel-Haenszel odds ratio (stratified by trial) was used.b Includes EPO-ANE-3018 and EPOANE3021MDS Trials: EPO-ANE-3018 and EPOANE3021

[TAE01G.rtf] [JNJ-7472179\Z_RMP\RMP_2015\RE_RMP_2015_EU\tae01g.sas] 26OCT2015, 09:04

In 2008, the Company performed an updated analysis of thrombotic vascular events (TVEs) in

cancer clinical trials. The analysis included 32 completed, randomised clinical trials of epoetin

alfa in patients with cancer, for which patient-level data were then available. These 32 trials,

which included a total of 7,444 patients, confirmed the previous analysis using a larger data set.

Thrombotic vascular events occurred in 118 (3.5%) of the 3,420 patients in the control group

compared with 260 (6.5%) of the 4,024 patients in the epoetin alfa group. The HR was

2.09 (95% CI: 1.67, 2.60) (Company data on file).


148

Postmarketing Experience:

The cumulative reporting rates for TVEs in the postmarketing setting as of 30 June 2015 are the

following, based on a cumulative postmarketing exposure of 4,575,083 PY: for all indications,

10 cases/100,000 PY; for the surgery indication: 126.3 cases/100,000 PY; for the cancer

indication: 32.7 cases/100,000 PY, and for the CRF indication: 2.5 cases/100,000 PY.

Nature of Risk:


Among the 2,046 patients treated in adult haemodialysis clinical trials with EPREX, there were

257 treatment-emergent TVEs. Of those 257 events, 205 events were considered to be moderate

to severe. One hundred fifty-four of the 257 TVE events were reported as serious adverse events.

Among the 5,610 patients treated in adult predialysis clinical trials with EPREX, there were

290 treatment-emergent TVEs. Of those 290 events, 226 events were considered to be moderate

to severe. Two hundred seven of the 290 TVE events were reported as serious adverse events.

Cancer

There is an increased risk for TVEs among patients with cancer who receive ESAs for the

treatment of chemotherapy-induced anaemia (CIA). Among the 5,827 patients treated in cancer

clinical trials with EPREX, there were 386 (6.62%) treatment-emergent TVEs. Of those

386 events, 209 (54%) events were considered to be Grade 3 events, while 6 (1.6%) of the

386 TVE events were reported as Grade 4 or more events.

The Company performed a predefined meta-analysis of trial data to evaluate selected clinically

important outcomes (mortality, TVE, and disease progression) for the cancer indication. The

primary data set used in the meta-analysis included 3,104 patients from 12 completed,

randomised, double-blinded, cancer trials for which patient-level data were available at the time

of the analysis (2004). The overall HR from the primary meta-analysis for clinically relevant

TVE occurrence for epoetin alfa compared with placebo was 1.44 (95% CI: 1.05, 1.98)

consistent with previous experience in this population (ODAC 2007a, 2007b, 2007c).

When trials were grouped by intended HGB target, trials that targeted a HGB concentration

beyond the correction of anaemia demonstrated a higher incidence of TVEs in both the control

and epoetin alfa groups. Thromboembolic vascular events occurred in 96 (4.3%) of

2,228 patients in the control group and 188 (8.2%) of 2,292 patients in the epoetin alfa group.

The HR was 1.98 (95% CI: 1.54, 2.55). For trials targeting HGB concentrations within the

current labelled indication, TVEs occurred in 22 (1.8%) of 1,192 patients in the control group

and 72 (4.2%) of 1,732 patients in the epoetin alfa group. The HR was 2.50 (95% CI: 1.54, 4.06).


149

Post-hoc, exploratory analyses of erythropoiesis-stimulating agent (ESA) treatment responders

versus ESA treatment non-responders suggest that patients who fail to respond to epoetin alfa

treatment after 4 or 8 weeks of therapy may have a higher risk for TVEs and adverse outcomes,

although it cannot be determined from available data whether this risk is due to epoetin alfa

treatment or inherent differences in the aggressiveness of the underlying malignancy that may

have resulted in nonresponsiveness (ODAC 2007a, 2007b, 2007c).

Trial EPO-ANE-4008, a randomised, open-label, multicentre trial evaluating TVEs in patients

with non-myeloid malignancies receiving chemotherapy and administered epoetin alfa once or

3 times a week for the treatment of anaemia, is completed. This trial demonstrated that in

anaemic patients with non-myeloid malignancies receiving chemotherapy, when used within

labelled guidance, the approved epoetin alfa dosing regimens of 450 IU/kg QW and

150 IU/kg 3 times per week (TIW) demonstrated comparable safety with respect to the incidence

TVEs (2.1% for the QW group and 3.8% for the TIW group; difference, -1.8%,

95% CI: -5.1% to 1.6%, p=0.248) as determined by an independent adjudication committee

through Week 16. The 2 regimens also demonstrated comparable efficacy with respect to

HGB response and RBC transfusion utilisation.

Surgery

Thrombotic vascular events are a recognised risk in patients undergoing elective orthopaedic

surgery (SmPC Section 4.4). In patients with a baseline HGB >13 g/dL, the possibility that

epoetin alfa treatment may be associated with an increased risk of postoperative TVEs cannot be

excluded. An analysis of adverse drug reactions (ADRs) conducted by the MAH across all

indications in 2010 confirmed this (ADR Report 2010). This review of 408 patients requiring

major, elective, orthopaedic surgery in 2 clinical studies demonstrated that the incidence of DVT

was higher in the epoetin alfa group (16/261 [6%]) compared with the placebo-control group

(6/147 [4%]); however, the customised group term “embolism and thrombosis” was comparable

(19/261 [7%)] versus 10/147 [7%], in the epoetin alfa and placebo groups, respectively).

Among the 1,352 patients treated in surgery clinical trials with EPREX, there were

78 treatment-emergent TVEs. Of those 78 events, 47 (60%) were considered to be moderate to

severe. Eighteen (23%) of the 78 TVE events were reported as serious adverse events.


Among the 102 patients treated in MDS clinical trials with EPREX, there were

2 treatment-emergent TVEs; one was Grade 1 severity and the other was Grade 3 severity. One

of the 2 TVE events was reported as a serious adverse event. In addition to these 2 cases, there

were 2 other cases, with reported terms of “sudden death” and “phlebitis” that were considered

TVEs in Trial EPOANE3021. In the case of sudden death, stroke was considered as a possible

cause of death by the investigator but was never confirmed. The event of phlebitis was distal

DVT in nature.


150

Background Incidence/Prevalence:


In a pooled analysis of 5 community-based cohorts from Europe and the United States, the

pooled risk for overall VTE associated with CKD was 1.54 (95% CI: 1.15-2.06) when comparing

individuals with CKD versus without CKD (Mahmoodi 2012a). The IR of VTE per 1,000 PY

was estimated to be 1.5, 1.9, and 4.5 for patients with normal kidney function, mildly decreased

renal function, and Stage 3 or 4 CKD, respectively, in a US study (Wattanaki 2008). A review

summarised that the prevalence of renal vein thrombosis is up to 37% in patients with

membranous glomerulonephritis, while DVT of the lower extremities can occur in up to 15% of

patients with nephrotic syndrome (Singhal 2006).

Cancer

The overall risk of thrombosis in patients with cancer is 7-fold that of patients without cancer

(Adess 2006). A review estimated the annual incidence of VTE to be 1 in 200 in a population of

patients with cancer (Lee 2003).


In a US study of postoperative thromboembolism in 2,043 patients who had a total hip

arthroplasty, the incidence of DVT was significantly lower in those who donated blood

preoperatively (9%) compared with those who had not (13.5%). Of those who donated blood,

0.3% developed postoperative pulmonary embolism compared with 0.7% in those who had not

(Bae 2001). Similar conclusions about a lower incidence of DVT in those who donated blood

preoperatively were also observed in a recent study in China (Lu 2013).

Surgery

A review of VTE in patients who underwent orthopaedic surgery indicated that without

thromboprophylaxis, DVT may occur in up to 60% of patients within 2 weeks after lower

extremity orthopaedic surgery (Kakkar 2013).


The majority of studies on thrombosis in MDS patients focus on specific drug exposures prior to

the occurrence of thrombosis. One study, however, observed that among 5,673 MDS patients,

212 patients had an incident DVT (Smith 2012).

Risk Groups or Risk Factors:

Established VTE risk factors include surgery, cancer, hospitalisation, immobilisation, obesity,

exogenous hormones, pregnancy and the puerperium, and inherited thrombophilia

(Wattanakit 2009). Orthopaedic surgery, especially hip and knee joint replacement, multiple

traumatisms, severe damage to the spine, or large fractures are risk factors for VTE. Patients


151

undergoing high-risk orthopaedic surgery who are not provided thromboprophylaxis have

increased risk for VTE (Meza Reyes 2012).

Potential Mechanisms:

The risk of TVEs is primarily related to hypercoagulability, altered blood flow, and endothelial

vascular lesions. Increased HCT is associated with increased blood viscosity, reduced venous

return, and increased platelet adhesion. Patients with HCT levels above the normal range for the

population are at an increased risk of TVEs. Relatively low plasma volume can also lead to

increased blood viscosity and a higher risk of TVEs (Brækkan 2010). The literature suggests that

epoetin alfa may transiently increase the number of circulating platelets and improve platelet

function (Tang 1998).

Preventability:

For all patients: HGB should be closely monitored due to the potential increased risk of TVEs

and fatal outcomes when patients are treated at HGB levels above the target for the indication of

use.

The reported risk of TVEs should be carefully weighed against the benefits to be derived from

treatment with EPREX, particularly in patients with pre-existing risk factors.

For CRF and cancer patients: Dose adjustments to maintain HGB values at the desired range

between 10 to 12 g/dL.

For cancer patients: closely monitor patients to ensure that the lowest approved dose of ESA is

used to provide adequate control of symptoms of anaemia.

For surgery patients: use of adequate antithrombotic prophylaxis during the perioperative period.

Impact on the Individual Patient:


May lead to increased mortality and morbidity. Patients may need surgical interventions or

procedures to treat thrombosis. Peripherally inserted central catheter lines may not be used for

haemodialysis because of the increased risk of TVEs.

Cancer

May lead to increased mortality and morbidity. Patients may need surgical interventions or

procedures to treat thrombosis (Bennett 2008).

Surgery

May lead to increased mortality and morbidity.

Potential Public Health Impact of Safety Concern:

May prolong hospitalisations and may require additional therapy to treat TVEs.


152

Evidence Source

Information regarding trials is provided in Annex 4.

Periodic Benefit-Risk Evaluation Report/Periodic Safety Update Report with data cutoff of

30 June 2015.

Adess 2006; ADR Report 2010; Bae 2001; Bennett 2008; Brækkan 2010; Kakkar 2013;

Lee 2003; Lu 2013; Mahmoodi 2012a; Meza Reyes 2012; ODAC 2007a, 2007b, 2007c;

Singhal 2006; Smith 2012; Tang 1998 Wattanakit 2008; Wattanakit 2009

MedDRA Terms:

Embolic and Thrombolic Events Standard MedDRA Query (SMQ)


153

Important Identified Risk – Pure Red Cell Aplasia

The risk of erythropoietin Ab-mediated PRCA was first identified in postauthorisation usage,

beginning in 1998 and peaking in 2002. However, in the entire clinical trial database, there were

only a total of 4 cases of PRCA reported in clinical trials, with 2 cases each reported for the

oncology and MDS indications, respectively.

Oncology

Only 1 case of PRCA (Grade 2 severity) has been reported to date in patients with cancer who

were receiving chemotherapy and treatment with EPREX in randomised clinical trials. The other

case (Grade 1 severity) occurred in a non-ESA-treated patient. Neither case was considered a

serious adverse event.


One case of PRCA was reported in each of the 2 clinical trials conducted in support of the MDS

indication.

An event with an actual reported term of anti-erythropoietin Ab positive was reported in

Trial EPOANE3021. The event was Grade 1 toxicity and reported in a subject in the epoetin alfa

group that had anti-erythropoietin Abs (1:20, 1.0% cpm [a positive Ab was 0.9% cpm in the

assay]) after Week 24. The event was considered related to the study agent and led to permanent

discontinuation. There were no signs of PRCA reported in the bone marrow; serum

erythropoietin remained detectable and reticulocytes were normal at the last available

measurement. There were no subjects with documented PRCA during the study.

In Trial EPO-ANE-3018, there was 1 event of PRCA reported in the placebo group. The event

was serious, Grade 3 toxicity, and considered by the investigator (while still blinded to treatment

allocation) to be possibly related to the study agent.


154

Frequency (Odds Ratio, 95% Confidence Interval), SAE Outcomes, and Severity of Pure Red Cell Aplasia in Randomised Controlled Clinical Trials, Clinical Trials Without Control, and All Clinical Trials






155


INDICATION: ONCOLOGY


OEOU21), NON-CISPLATIN (I88-037, OEO-U22 and OEO-U23), AGO/NOGGO (EPO-GER-8), EP92-002,EPO-CAN-15, EPO-CAN-17, EPO-CAN-20, EPO-CAN-203, EPO-CAN-303, EPO-GBR-4, EPO-GBR-7, EPO-GER-20, EPO-GER-22, EPO-GOG-191, EPO-INT-1 (2574-P-416), EPO-INT-10 (EPO-C111-457), EPO-INT-2 (CC2574-P-467), EPO-INT-3 (2574-P-034), EPO-INT-45, EPO-INT-47, EPO-INT-49, EPO-INT-50, EPO-INT-51 (EPO-CA-484), EPO-INT-76 (EPO-CA-489), EPO-J89-040 (J89-040), EPO-N93-004 (N93-004), EPO-P-169 (2574-P-169), EPO-P-174 (CC2574-P-174), MOEBUS, OBE/EPO-INT-03, PR00-03-006, PR00-27-005, PR98-27-008, PR99-11-034/044, PRI/EPO-NED-17, RTOG/PR99-03-046 (PR99-03-046), EPO-CAN-29, EPO-ANE-3010





156








Cumulatively, as of 30 June 2015, there have been 334 Ab-positive PRCA cases identified in

patients with CRF. The majority (193 cases, 58%) involved exposure to EPREX in PS-80

uncoated stopper prefilled syringes (withdrawn from the market in 2004). Forty-one (37%) of the

111 cumulative cases of Ab-positive PRCA exposed to SC use of the currently marketed EPREX

in PS-80 coated-stopper prefilled syringes only were reported from Thailand and 70 (63%) cases

were reported outside of Thailand. The corresponding PRCA reporting rate in Thailand is unique

to that country, is not EPREX-specific, and does not reflect the situation in the rest of the world.

The Company’s assessment of the worldwide reporting rate excluding Thailand in patients with

CRF exposed to SC use of EPREX in PS-80 coated-stopper prefilled syringes

(6.8 cases per 100,000 PY) more accurately reflects the baseline risk of Ab-positive PRCA

associated with EPREX.


157

The Company has worked with the Thailand Health Authority and the Thailand Nephrology and

Haematology Societies to identify possible reasons for the Thailand-specific reporting rate,

including support of the Thai Registry, EPOANE4076. A total of 4,018 patients from

63 hospitals have been enroled in the Thai registry (EPOANE4076) since 2008. Enrolment was

stopped by the primary investigator in June 2013. Of the 4,018 patients, approximately

400 patients (10%) received EPREX, while the remaining patients received non-EPREX brand

ESA. Nine non-EPREX-brand ESA-related PRCA cases were reported, with an incidence of

anti-r-HuEPO-associated PRCA case in Thailand of 1.7 cases per 1,000 PY exposure. The

average exposure time was 13.6 months. No cases of Ab-mediated PRCA were identified with

EPREX. Furthermore, the Company has an extensive worldwide pharmacovigilance monitoring

programme for PRCA and has not detected any similar PRCA case clusters occurring at a single

institution elsewhere in the world over the last 10 years.

Nature of Risk:

Pure red cell aplasia is a risk identified from postmarketing pharmacovigilance, not clinical

trials. Cases of PRCA and reporting rates are proactively monitored and reported to health

authorities periodically.

To date, only 2 cases of PRCA have been reported among EPREX-treated patients in clinical

trials. Among the 5,827 patients treated in the cancer clinical trials with EPREX, there was

1 treatment-emergent event of PRCA in a patient with cancer who was receiving chemotherapy

and treatment with EPREX. The other case was reported in a patient participating in a clinical

trial for the MDS indication. Among the 102 patients treated in the MDS clinical trials with

EPREX, there was 1 serious adverse event with an actual reported term of anti-erythropoietin

positive (Grade 1 severity), for which PRCA was not confirmed.

The incidence of erythropoietin Ab-mediated PRCA associated with EPREX was elevated above

the baseline rate associated with all ESAs for the period from 1998 to 2003 (RMP epoetin alfa

2005). The results of extensive quality, nonclinical, and clinical/epidemiologic investigations

clearly support the conclusion that the transient increase in erythropoietin Ab-mediated PRCA

between 1998 and 2003 was product-specific to EPREX and the increase over the background

rate was associated with the use of 1 specific product presentation: the PS-80 EPREX

formulation in prefilled syringes with uncoated rubber stoppers (1,000 IU to 4,000 IU and

10,000 IU strengths). The PS-80 EPREX vials and prefilled syringes in the 5,000 IU to 9,000 IU

strengths have always been in coated-stopper presentations since their introduction in 1999 and

2000, respectively. Following the completion of a worldwide product recall in March 2004, the

PS-80 EPREX formulation has been used exclusively in coated-stopper presentations. Since the

introduction of this product presentation, the increased incidence associated with the PS-80

EPREX formulation in prefilled syringes with uncoated rubber stoppers has been resolved. The

focus of this RMP is to describe the period of increased EPREX-specific PRCA, PRCA trends

associated with the currently available PS-80 EPREX formulation in prefilled syringes with

coated rubber stoppers, as well as ongoing pharmacovigilance and risk mitigation activities to

ensure PRCA associated with the PS-80 EPREX formulation in prefilled syringes with coated

rubber stoppers approximates the baseline risk associated with all ESAs.


158

An immunogenicity surveillance registry (Study EPO-ANE-4014) was conducted to provide

assurance that the SC PS-80 EPREX formulation using coated stoppers had an acceptable

immunogenic safety profile. The primary objective for this registry was to estimate the IR of

erythropoietin Ab-mediated PRCA with SC exposure to the PS-80 formulation of EPREX and to

compare this IR to that with SC exposure to other currently marketed recombinant erythropoietin

products (epoetin beta [NeoRecormon®] and darbepoetin alfa [Aranesp®]) with adjustment for

duration of exposure. Patients were to be observed for the development of PRCA for up to

3 years.

Study EPO-ANE-4014 enroled a total of 15,333 patients. There were 8,377 PY of exposure to

EPREX and 14,286 PY of exposure to other ESAs. There were 3 cases of erythropoietin

Ab-mediated PRCA with EPREX and 2 cases with other ESAs (1 case with Aranesp and 1 case

with NeoRecormon) reported during the conduct of the registry. When comparing the IRs based

on exposed time, the rate for the 3 EPREX cases was 35.8/100,000 PY, the rate for the

2 Aranesp/NeoRecormon cases combined was 14.0/100,000 PY, and the rate ratio was

2.6 (95% CI: 0.43, 15.31). The 90% and 95% CIs for the IRs overlap. Confidence intervals for

the rate ratio overlap unity. The IR differences were not statistically significant (p-value was

greater than 0.05).


The baseline erythropoietin Ab-mediated PRCA rate expected with all ESAs has not been

quantified in interventional clinical trials. It is the Company’s view that the PRCA reporting

rates for EPREX cannot be directly compared with rates for other recombinant ESAs that are

based upon spontaneous reports with different methods of case classification/adjudication,

estimation, stimulation, selected time periods, and routes of administration.


Recent findings from data collected on 15,333 patients with CKD, aged 18 years or older,

enroled in the PRIMS observed 5 cases of confirmed Ab-mediated PRCA during the 3-year

follow-up period. This translated to an IR of 35.8/100,000 PY for EPREX versus 14.0/100,000

PY (95% CI 1.7–50.6) for NeoRecormon®/Aranesp®. The incidence of erythropoietin Ab-

mediated PRCA with EPREX was not significantly different versus comparator ESAs (rate ratio:

2.56; 95% CI 0.43–15.31). An analysis based on observed time produced similar findings.


159

The prevalence of pre-existing non-neutralising anti-ESA Abs in clinical trials of

1,235 nephrology patients was 5.75%, and the developing Ab rate in these patients was 2.43%.

However, 101 of the 1,235 nephrology patients (8.2%) were determined to develop anti-ESA Ab

after ESA treatment, although none of these patients demonstrated any signs of developing

Ab-mediated PRCA. A small number of patients (1.7% in nephrology) had pre-existing Abs

(baseline positive) that were post-dose Ab negative. Patients that had progressed to Ab-mediated

PRCA were noted to have high Ab concentrations with neutralising activity and a diverse

Immunoglobulin G (IgG) subtype (Barger 2012).

Cancer

According to a review on anti-erthropoietin Abs and PRCA, no cases of epoetin-induced PRCA

had been reported in cancer patients on chemotherapy at the time of publication (Rossert 2004).

Surgery

The incidence and prevalence data on PRCA and patients undergoing orthopaedic surgery are

not detailed in the literature.


Myelodysplastic syndrome with PRCA was identified in a total of 16 (2.9%) patients among

550 consecutive adult MDS patients diagnosed in a US hospital (Wang 2007).

Risk Groups or Risk Factors:


Pure red cell aplasia has been reported in patients with CRF who were receiving epoetin alfa by

SC administration. Risk factors for Ab-mediated PRCA can be related to both patient and

product (erythropoietin). Patient-related factors associated with developing Ab-mediated PRCA

include skin reactions, immune status, and treatment history. Product-related factors that could

impact immunogenicity include sequence variations in proteins, degree and nature of protein

glycosylation, manufacturing process, handling and storage, and components and properties of

the product formulation (Macdougall 2005). In addition to these, a more recent review of

Ab-mediated PRCA in CKD patients receiving ESAs included genetic background, age, sex,

comorbidities, and concomitant medications as additional patient-related factors, while

product-related factors also included leachates and Tungsten-induced aggregation in addition to

treatment duration and route of administration (Macdougall 2012).

Cancer

Risk factors for developing PRCA and patients with cancer are not detailed in the literature.

Surgery

Risk factors for developing PRCA and patients undergoing orthopaedic surgery are not detailed

in the literature.


160


Development of Abs to erythropoietin causes an isolated disorder of erythropoiesis that leads to a

severe, isolated anaemia with sudden onset. Epoetin alfa is a recombinant version of a human

protein, and therefore, the mechanism is likely related to autoimmunity and disrupting

B-cell tolerance. The mechanisms by which tolerance is disrupted are not entirely understood.

The presence of aggregates may be a key factor in triggering activation of autoreactive B cells:

the periodicity of self-antigens present in protein aggregates is similar to the repeated

self-epitope structure of viral capsids that can directly activate B cells (Schellekens 2006,

Van Beers 2010, Macdougall 2012).

The timing of the increase in the rate of PRCA in 1998 was consistent with the introduction of

the EPREX PS-80 formulation and is consistent with the formulation switch. Further

investigations demonstrated that this formulation was associated with the appearance of

leachates in EPREX prefilled syringes that used an uncoated rubber stopper. These leachates

have been demonstrated in mouse studies to enhance the immune response to foreign protein in a

dose-dependent fashion (Ryan 2006).

The results of extensive quality, nonclinical, and clinical/epidemiologic investigations clearly

support the conclusion that the transient increase in PRCA between 1998 and 2003 was

product-specific to EPREX, and the increase over the background rate was associated with the

use of 1 specific product presentation: the PS-80 EPREX formulation in prefilled syringes with

uncoated rubber stoppers (1,000 IU-4,000 IU and 10,000 IU strengths) (Boven 2005).

Anaemia from PRCA can be managed with blood transfusion and is reversible for many patients

with immunosuppressive treatments (Casadevall 2005; Eckardt 2003).

Preventability:

Since the PS-80 EPREX formulation has been available exclusively in coated-stopper

presentations, the IR of erythropoietin Ab-mediated PRCA associated with SC EPREX use in

patients with CKD has dropped and now approximates the background/baseline level.

Immunogenicity to any therapeutic protein is potentially increased by product degradation and

aggregation. To minimise the risk of this, the Company maintains and monitors an appropriate

continuous cold chain for storage and handling of EPREX from point of manufacture to the final

distribution agent.

In patients with CRF where IV access is routinely available (haemodialysis patients),

administration by the IV route is preferable. Such IV use will further reduce the baseline risk,

because the IV route is generally associated with the lowest risk of immunogenicity for

therapeutic proteins.


161

Patients with CRF treated with epoetin alfa by the SC route should be monitored regularly for

loss of efficacy, defined as absent or decreased response to epoetin alfa treatment in patients who

previously responded to such therapy. This is characterised by a sustained decrease in HGB

despite an increase in epoetin alfa dosage. In patients developing sudden lack of efficacy defined

by a decrease in HGB (1 to 2 g/dL per month) with increased need for transfusions, a

reticulocyte count should be obtained and typical causes of non-response (eg, iron, folate, or

Vitamin B12 deficiency, aluminium intoxication, infection or inflammation, blood loss, and

haemolysis and bone marrow fibrosis of any origin) should be investigated.

A paradoxical decrease in HGB and development of severe anaemia associated with low

reticulocyte counts should prompt to discontinue treatment with EPREX and perform

anti-erythropoietin Ab testing. A bone marrow examination should also be considered for

diagnosis of PRCA.

No other ESA therapy should be commenced because of the risk of cross reaction.

Antibody-mediated PRCA has been reported after months to years of mostly SC epoetin

treatment mainly in patients with CRF. Very rarely, cases have been reported with IV epoetin

use as well. Cases have also been reported in patients with hepatitis C treated with interferon and

ribavirin, when ESAs are used concomitantly. EPREX is not approved for the management of

anaemia associated with hepatitis C.


Patients may develop severe erythropoietin-resistant anaemia that may require repeated

transfusions. Patients may develop PRCA, which needs to be treated with

immunosuppressive/immunomodulatory therapies such as cyclosporine or prednisone.

Alternatives to ESA treatment include RBC transfusions, which have inherent risks.


At the peak incidence, EPREX product-specific PRCA was a rare event

(>1/10,000, <1/1,000 PY), with a cumulative reporting rate of 46.9/100,000 PY. The cumulative

reporting rate of Ab-positive PRCA for EPREX is 17.3 cases per 100,000 PYs for SC use

(10.5 cases per 100,000 PY excluding Thailand) and 0.2 cases per 100,000 PYs for IV use.

Anaemia from PRCA can be managed by blood transfusions and is reversible for many patients

with immunosuppressive treatment alone or with immunosuppressive treatment associated with

renal transplantation (Eckardt, 2003; Bennett 2005). After Ab levels have decreased, patients can

be treated again with IV EPREX. The public health impact is, therefore, considered low.


162

Evidence Source:

Study EPO-ANE-4014 (PRIMS), Annex 4.


30 June 2015.

Semiannual Immunogenicity Report, August 2015.

Barger 2012; Bennett 2005; Boven 2005; Casadevall 2005, Eckardt 2003; Macdougall 2005;

Macdougall 2012; RMP epoetin alfa 2005; Rossert 2004; Ryan 2006; Schellekens 2006;

Van Beers 2010; Wang 2007

MedDRA Terms:

The following preferred terms were used for PRCA: anti-erythropoietin Ab, anti-erythropoietin

Ab positive, Ab test abnormal, Ab test positive, aplasia pure red cell, drug-specific Ab present,

inhibiting Abs, neutralising Abs.


163

Important Identified Risk – Hypertension/Hypertensive Crisis

Frequency (Odds Ratio, 95% Confidence Interval), SAE Outcomes, and Severity of Hypertension in Randomised Controlled Clinical Trials, Clinical Trials Without Control, and All Clinical Trials


Randomised Controlled Trials b 97 46NAny Treatment-Emergent Event, n (%) 5 (5.15%) 0 (0.00%) N/AOutcome (Based on Serious AEs) 0 0Fatal 0 (0.00%) 0 (0.00%)Hospitalised 0 (0.00%) 0 (0.00%)Not Recovered 0 (0.00%) 0 (0.00%)Recovered 0 (0.00%) 0 (0.00%)N/A 0 (0.00%) 0 (0.00%)Severity, n (%)Mild 2 (2.06%) 0 (0.00%)Moderate 2 (2.06%) 0 (0.00%)Severe 1 (1.03%) 0 (0.00%)Unknown 0 (0.00%) 0 (0.00%)Missing 0 (0.00%) 0 (0.00%)



AE=adverse event; CI=confidence interval; ESA=erythropoiesis-stimulating agent; N/n=number; N/A=not applicablea The stratified Mantel-Haenszel odds ratio (stratified by trial) was used.b Includes EP86-001 (CEO-C01), EP86-004c Includes EPO-CAN-1, EPO-CAN-13, EPO-INT-37, EPO-INT-68, EPO-INT-77, EPO-ITA-2, ZEO-107 (CCP107P108),

ZEO-121 (CC2574P121), ZEO-S01 (CCP102P103)

Chronic Renal Failure – Dialysis Trials: EP86-001 (CEO-C01), EP86-004, EPO-CAN-1, EPO-CAN-13, EPO-INT-37, EPO-INT-68, EPO-INT-77, EPO-ITA-2, ZEO-107 (CCP107P108), ZEO-121 (CC2574P121), ZEO-S01 (CCP102P103)



164


INDICATION: CHRONIC RENAL FAILURE - PREDIALYSISEpoetin alfa (N=5610) Non-ESA control (N=325) Odds Ratio a (95% CI)









165







166


INDICATION: ONCOLOGY


OEOU21), NON-CISPLATIN (I88-037, OEO-U22 and OEO-U23), AGO/NOGGO (EPO-GER-8), EP92-002, EPO-CAN-15, EPO-CAN-17, EPO-CAN-20, EPO-CAN-203, EPO-CAN-303, EPO-GBR-4, EPO-GBR-7, EPO-GER-20, EPO-GER-22, EPO-GOG-191, EPO-INT-1 (2574-P-416), EPO-INT-10 (EPO-C111-457), EPO-INT-2 (CC2574-P-467), EPO-INT-3 (2574-P-034), EPO-INT-45, EPO-INT-47, EPO-INT-49, EPO-INT-50, EPO-INT-51 (EPO-CA-484), EPO-INT-76 (EPO-CA-489), EPO-J89-040 (J89-040), EPO-N93-004 (N93-004), EPO-P-169 (2574-P-169), EPO-P-174 (CC2574-P-174), MOEBUS, OBE/EPO-INT-03, PR00-03-006, PR00-27-005, PR98-27-008, PR99-11-034/044, PRI/EPO-NED-17, RTOG/PR99-03-046 (PR99-03-046), EPO-CAN-29, EPO-ANE-3010





INDICATION:AUTOLOGOUS BLOOD DONATIONEpoetin alfa (N=402) Non-ESA control (N=242) Odds Ratio a (95% CI)



ABD=autologous blood donation; AE=adverse event; CI=confidence interval; ESA=erythropoiesis-stimulating agent; N/n=number; N/A=not applicablea The stratified Mantel-Haenszel odds ratio (stratified by trial) was used.b Includes CC 2574-P-159, CC 2574-P-165, CC 2574-P-166, H87-017, H87-036, I88-027, I88-058ABD Trials: CC 2574-P-159, CC 2574-P-165, CC 2574-P-166, H87-017, H87-036, I88-027, I88-058.



167






AE=adverse event; CI=confidence interval; ESA=erythropoiesis-stimulating agent; N/n=number; N/A=not applicablea The stratified Mantel-Haenszel odds ratio (stratified by trial) was used.b Includes EPO-APO2-474, EPO-INT-34 (EPO-AP02-478), CEO-C04, H87-083, J89-001, M92-011, PR97-19-002 (spine)c Includes N93-057

Surgery Trials: EPO-APO2-474, EPO-INT-34 (EPO-AP02-478), CEO-C04, H87-083, J89-001, M92-011, N93-057, PR97 19 002 (spine)



168








The cumulative reporting rate for hypertension (which may include hypertensive crisis or other

related terms) in the postmarketing setting is 4.3 cases per 100,000 PY based on 4,575,083 PY of

cumulative exposure through 30 June 2015.


169

Nature of Risk:


A history of hypertension is a risk factor for CHF in patients on dialysis. Among the 2,046 adult

patients treated in adult haemodialysis trials with EPREX, there were 345 treatment-emergent

hypertension events. Of those 345 hypertension events, 166 (48%) were considered to be

moderate to severe. Twenty-nine (<1%) of the 345 hypertension events were reported as serious

adverse events. Among the 5,610 adult patients treated in adult predialysis clinical trials with

EPREX, there were 688 treatment-emergent hypertension events. Of those 688 hypertension

events, 381 (55%) were considered to be moderate to severe. Sixty (<1%) of the

688 hypertension events were reported as serious adverse events.

Cancer

Among the 5,827 adult patients treated in cancer clinical trials with EPREX, there were

157 treatment-emergent hypertension events. Of those 157 events, 60 (38%) were Grade 2 and

21 (13%) were Grade 3. Five (3%) of the 157 hypertension events were reported as serious

adverse events.


Of the 402 patients treated in the ABD clinical trials with epoetin alfa, there were only 6 (1.49%)

treatment-emergent hypertension events reported. One of the events was mild in severity, while

severity was missing for the other 5 events.

Surgery

Among the 1,352 adult patients treated in orthopaedic surgery clinical trials with EPREX, there

were 119 treatment-emergent hypertension events. Of those 119 events, 60 (50%) were

considered to be moderate to severe. There were no reports of hypertension as serious adverse

events in EPREX-treated surgical patients. Antiplatelet therapy may prevent the development of

hypertension in patients treated with epoetin alfa (Caravaca 1994).


Among the 102 adult patients treated in the MDS clinical trials with EPREX, there were

6 treatment-emergent hypertension events. Of those 6 events, 3 events were Grade 1, 1 event was

Grade 2, and 2 events were Grade 3. None of the hypertension events were reported as serious

adverse events.



Arterial hypertension develops in up to 80% of renal transplant recipients (Basić-Jukić 2007). In

a large nationally representative sample of adults in England, hypertension was prevalent in

25.4% of patients with CKD (Kearns 2013). Hypertension prevalence by CKD stage is provided

in a US national survey of non-institutionalised adults, which estimates that hypertension occurs

in 35.8% of Stage 1, 48.1% of Stage 2, 59.9% of Stage 3, and 84.1% of Stage 4 to 5 patients with


170

CKD (USRDS 2010). Hypertension is found in more than 50% of paediatric patients with CKD,

although its prevalence varies according to the cause of CKD (Van DeVoorde 2011). In a large

nationally representative sample of adults in England, hypertension was prevalent in 4.5% of

patients with mildly impaired eGFR, 63.9% of those with Stage 3 to 5 CKD, and 79.3% of those

with Stage 5 CKD (Jameson 2014).

Cancer

Among patients with cancer, hypertension has been observed to be the most common

comorbidity with a prevalence of 37% (Piccirillo 2004). However, the prevalence of 29% prior

to chemotherapy was found to be similar to the general population (Maitland 2010). A

restrospective cohort study was conducted to estimate IRs of new-onset hypertension in adult

cancer patients identified from the Varian Medical Oncology outpatient database in the United

States. New-onset hypertension was observed in about one-third of 25,090 patients with various

types of cancer. The IRs of severe and crisis-level hypertension, respectively, were the highest in

patients with gastric (18.5 cases per 100 PY, 5.6 per 100 PY) and ovarian cancer

(20.2 per 100 PY, 4.8 per 100 PY). The highest IR of moderate hypertension was observed in

patients with renal cancer (46.7 per 100 PY). Across all cancers, chemotherapy exposure was

associated with a 2- to 3.5-fold increase in risk of any degree of hypertension compared with

periods of no chemotherapy; higher hypertension levels demonstrated greater variability in RRs

by type and line of therapy but indicated an overall increase associated with chemotherapy

exposure (Fraeman 2013).

Surgery

According to US NHDS data, the prevalence of hypertension among patients undergoing total

arthroplasty from 1990 to 2004 was 37.54% (Liu 2009). Another study that included patients in

the United Kingdom reported that 49.3% of TKR patients also had hypertension (Oleske 2014).


In a US study of 600 MDS patients, approximately 55% of patients were diagnosed with a

disorder of the cardiovascular system, with hypertension being the most common comorbidity at

27% (Naqvi 2011). A small retrospective chart review of 26 patients who had received a

diagnosis of both chronic myeloid disorders and pulmonary hypertension observed that 2 patients

had MDS (Dingli 2001). Another study of 88 MDS patients observed hypertension to be present

in 45.4% of patients (De Roos 2010).

Risk Factors:

Risk factors for hypertension include increasing age, African-American race, family history of

hypertension, being overweight or obese, physical inactivity, tobacco use, dietary factors

(excess sodium, insufficient potassium, and vitamin D), stress, and alcohol (Mayo Clinic, high

blood pressure 2012).


171


Postulated mechanisms for epoetin alfa-induced hypertension include increased viscosity or

vasoconstrictive responses due to the correction of anaemia (Kanbay 2007). Experiments

designed to study the vascular sequelae (hypertension and thrombosis) of epoetin alfa treatment

have revealed that endothelial cells have large numbers of epoetin alfa receptors and that epoetin

alfa enhances their proliferation and migration in vitro (Lappin 2007).

Preventability:

In all patients receiving epoetin alfa, blood pressure should be closely monitored and controlled

as necessary. Epoetin alfa should be used with caution in the presence of untreated, inadequately

treated, or poorly controllable hypertension. It may be necessary to add or increase

antihypertensive treatment. If blood pressure cannot be controlled, epoetin alfa treatment should

be discontinued.

Hypertensive crisis with encephalopathy and seizures, requiring the immediate attention of a

physician and intensive medical care, have occurred also during epoetin alfa treatment in patients

with previously normal or low blood pressure. Particular attention should be paid to sudden

stabbing migraine-like headaches as a possible warning signal.

In patients with CRF, the rate of increase in HGB should not exceed 2 g/dL (1.25 mmol/l) per

month to minimise risks of hypertension. Maintenance HGB concentrations should not exceed

the upper limit of the HGB concentration range as recommended in Section 4.2 of the SmPC

(12 g/dL [7.5 mmol/L]). In clinical trials, an increased risk of death and serious cardiovascular

events was observed when ESAs were administered to achieve a HGB concentration greater than

12 g/dL. In patients with CRF and cancer, HGB concentrations should be monitored regularly

until a stable level is achieved, and periodically thereafter.


There is a potential for increased morbidity and mortality.


Chronic renal failure is a global public health concern, and there is emerging a strong

relationship between CRF and increased CVD risk. Chronic renal failure in the presence of other

comorbidities such as hypertension and Type 2 diabetes mellitus can lead to early progression to

ESRD (Stage V CRF) and confer a greater risk for CVD morbidity and mortality than is seen

among patients with CRF who do not have these comorbidities (Yerram 2007).

In general, hypertension is very prevalent in the patient population being treated with EPREX,

therefore, the additional public health impact associated with this safety risk is considered low.


172

Evidence Source:

Information regarding trials is provided in Annex 4.


30 June 2015.

SmPC

Basić-Jukić 2007; Caravaca 1994; DeRoos 2010; Dingli 2001; Fraeman 2013; Jameson 2014;

Kanbay 2007; Kearns 2013; Lappin 2007; Liu 2009; Maitland 2010; Mayo Clinic 2012, high

blood pressure; Naqvi 2011; Oleske 2014; Piccirillo 2004; USRDS 2010; Van DeVoorde 2011;

Yerram 2007

MedDRA Terms:

Hypertension SMQ; scope=narrow


173

Important Potential Risks

Important Potential Risk – Disease Progression

Frequency (Odds Ratio, 95% Confidence Interval), SAE Outcomes, and Severity of Disease Progression in Randomised Controlled Clinical Trials, Clinical Trials Without Control, and All Clinical Trials


Randomised Controlled Trials b 5323 4719NAny Treatment-Emergent Event, n (%)

292 (5.49%) 249 (5.28%) 1.00 (0.81,1.23)

Outcome (Based on Serious AEs) 74 48Fatal 11 (0.21%) 5 (0.11%)Hospitalised 0 (0.00%) 0 (0.00%)Not Recovered 29 (0.54%) 17 (0.36%)Recovered 18 (0.34%) 15 (0.32%)N/A 16 (0.30%) 11 (0.23%)Severity, n (%)Grade=1 7 (0.13%) 6 (0.13%)Grade=2 34 (0.64%) 27 (0.57%)Grade=3 117 (2.20%) 79 (1.67%)Grade>=4 0 (0.00%) 1 (0.02%)Unknown 134 (2.52%) 136 (2.88%)

Trials without control c 504 0NAny Treatment-Emergent Event, n (%)

61 (12.1%) 0 (0.00%) N/A


Combined (All Trials) 5827 4719NAny Treatment-Emergent Event, n (%)

353 (6.06%) 249 (5.28%)



174



OEOU21), NON-CISPLATIN (I88-037, OEO-U22 and OEO-U23), AGO/NOGGO (EPO-GER-8), EP92-002,EPO-CAN-15, EPO-CAN-17, EPO-CAN-20, EPO-CAN-203, EPO-CAN-303, EPO-GBR-4, EPO-GBR-7, EPO-GER-20, EPO-GER-22, EPO-GOG-191, EPO-INT-1 (2574-P-416), EPO-INT-10 (EPO-C111-457), EPO-INT-2 (CC2574-P-467), EPO-INT-3 (2574-P-034), EPO-INT-45, EPO-INT-47, EPO-INT-49, EPO-INT-50, EPO-INT-51 (EPO-CA-484), EPO-INT-76 (EPO-CA-489), EPO-J89-040 (J89-040), EPO-N93-004 (N93-004), EPO-P-169 (2574-P-169), EPO-P-174 (CC2574-P-174), MOEBUS, OBE/EPO-INT-03, PR00-03-006, PR00-27-005, PR98-27-008, PR99-11-034/044, PRI/EPO-NED-17, RTOG/PR99-03-046 (PR99-03-046), EPO-CAN-29, EPO-ANE-3010





175




4 (3.92%) 1 (1.89%) 2.17 (0.24,20.0)



4 (3.92%) 1 (1.89%)




Postmarketing Experience

As of 30 June 2015, a cumulative search of the postmarketing database identified 35 cases of

disease progression in patients with cancer. Of these cases, 21 cases reported a fatal outcome.

The cumulative reporting rate of disease progression for the cancer indication in the

postmarketing setting is 0.8 cases per 100,000 PY, based on 4,575,083 PYs of cumulative

exposure through 30 June 2015.


176

Nature of Risk:

Cancer

This important potential risk only involves patients treated for CIA.

None of the Company’s supportive-care trials has rigorously assessed tumour outcomes utilising

methods that would be appropriate to the development of cancer therapeutic agents. In general,

trials have lacked the necessary tumour and treatment homogeneity for this assessment because

they were designed to evaluate haematologic endpoints, not tumour outcome, as the primary

efficacy measure. Response-based endpoints are difficult to interpret because of the requirement

that patients enter the trial only after becoming anaemic during chemotherapy administration

rather than entering at the commencement of chemotherapy. Therefore, PFS from the time of

first epoetin alfa administration, as measured in these supportive-care trials, is actually quite

different from PFS normally reported in trials of therapeutic cancer agents (where it is measured

from the onset of chemotherapy treatment).

Tumour progression as the basis for excess mortality observed in some clinical trials remains an

unresolved issue. Although theoretically plausible, it has not been consistently supported by

preclinical data or in clinical trials, notwithstanding methodologic limitations inherent to

supportive-care cancer trials. Plausible alternatives (eg, TVEs at high HGB targets) need also to

be considered as a potential cause of excess mortality seen in a few trials.

Comprehensive analyses of patient-level data from controlled clinical trials with epoetin alfa,

when used in the setting of CIA, demonstrate a neutral effect on overall survival and tumour

progression while demonstrating clear benefit in terms of reducing the need for blood transfusion

(ODAC 2007a, 2007b, 2007c).

The Company is evaluating the impact of epoetin alfa on tumour outcome including PFS and

survival in an appropriately designed clinical trial (Trial EPO-ANE-3010).

Among the 5,827 adult patients treated in cancer trials with EPREX, there were

353 treatment-emergent disease-progression events. Of those 353 events, 149 (42%) were

Grade 3 and 15 (4%) were Grade 4. One hundred and fifteen of the 353 disease-progression

events were reported as serious adverse events.


Among the 102 adult patients treated in MDS clinical trials with EPREX, there were

4 treatment emergent disease-progression events. Of those 4 events, 2 (50%) were Grade 2

severity, 1 (25%) was Grade 3 severity, and 1 (25%) was Grade 4 severity. All of the

disease-progression events were reported as serious adverse events.

In the Phase 3 MDS trial (EPOANE3021), the individual treatment-emergent adverse event

terms used by the investigator to report diseases were different from the pooled-analysis terms

used in above clinical trial data. Based on actual visit dates, 6 (7.1%) patients in the epoetin alfa

group and 4 (8.9%) patients in the placebo group had disease progression reported during the


177

first 24 weeks of the study. Individual treatment-emergent adverse events used by the

investigators to report disease progression were coded as MDS (2 patients in the epoetin group),

acute myelogenous leukaemia (AML, 1 patient in the epoetin alfa group, 2 patients in the

placebo group), refractory anaemia with excess blasts (1 patient in each group), leukaemia

(1 patient in the epoetin alfa group), thrombocytopaenia (1 patient in the epoetin alfa group), and

disease progression (1 patient in the placebo group). During the entire trial period, 14 (16.5%)

patients in the epoetin alfa group and 4 (8.9%) patients in the placebo group had disease

progression. No patients in the placebo group had disease progression after the first 24 weeks.

However, only 1 of 45 patients in placebo group entered into the extension phase and had follow

up after Week 28. Based on actual visit dates, an additional 8 (9.4%) patients in the epoetin alfa

group had disease progression reported after the first 24 weeks of the trial. Individual

treatment-emergent adverse events used by the investigators to report disease progression after

the first 24 weeks were coded as MDS (3 patients), AML (1 patient), and disease progression

(4 patients).

Overall, among the subjects who experienced disease progression, there were 5 who progressed

to AML (3 [3.5%] in the epoetin alfa group and 2 [4.4%] in the placebo group); all progressions

to AML occurred prior or at Week 24.



The risk of disease progression is associated with the cancer indication only.

Cancer

Progression of cancer can vary by cancer type. For example, according to a review of ductal

carcinoma in situ cases, results from large clinical trials and follow-up trials suggest that, if left

untreated, up to 50% of ductal carcinoma in situ lesions progress to invasive disease, and time

for progression may be up to 4 decades (Saunders 2005; Collins 2005; Jones 2006). In

non-muscle invasive bladder cancer, progression can occur in 45% of patients at stage pT1 and

carcinoma in situ (van Rhijn 2009).

Surgery

The risk of disease progression is associated with the cancer indication only.


In a retrospective analysis of 856 patients with low- or intermediate-1-risk MDS, only 10% of

patients in this series transformed to AML (Garcia-Manero, 2010), while a review noted that the

risk of progression to AML is 25% to 35% at 5 years. Specifically, the median time to 25% AML

evolution is 9.4 years for low risk, 2.5 years for intermediate risk, 1.7 years for high risk, and

0.7 years for very high-risk MDS disease (Fenaux 2014).


178

Risk Factors:

Risk factors of disease progression depend on the type of cancer. Disease progression in

oncology patients can depend on environmental and psychological factors.


Preclinical in vitro and in vivo data do not provide convincing evidence that erythropoietin

promotes tumour growth and proliferation. Although there is no convincing evidence from

clinical trials that epoetin alfa promotes tumour growth, theoretical mechanisms include:

1) direct tumour promotion through an interaction with epoetin receptors expressed on the

surface of tumour cells, 2) promotion of tumour vascularisation leading to promotion of tumour

growth.

Preventability:

The perceived increased risk of disease progression or death with epoetin alfa treatment was

observed in settings where either epoetin alfa was administered to achieve HGB levels beyond

the correction of anaemia (>12 g/dL), or in the setting of cancer-induced anaemia in patients not

receiving concomitant anticancer treatment and in the setting of patients with head and neck

cancer receiving radiotherapy only.


Decreased survival in patients with cancer.


Decreased PFS time in patients with cancer.

Evidence Source:

Information regarding cancer trials is provided in Annex 4.

Collins 2005; Fenaux 2014; Garcia-Manero 2010; Jones 2006; ODAC 2007a, 2007b, 2007c;

Saunders 2005; van Rhijn 2009.

MedDRA Terms:

The following preferred terms were used for disease progression: condition aggravated, disease

progression, malignant neoplasm progression, neoplasm progression


179

Important Potential Risk – Survival Impact

Survival data were not collected as an endpoint in surgery clinical trials. Therefore a frequency

table for this potential risk is not provided for the surgery indication.

Survival or mortality data were collected in some of the cancer and CRF clinical trials. However,

survival in patients with cancer mainly depends on the underlying tumour type and patients in

different cancer trials had very different tumour types. In addition, a mortality safety signal was

only observed in cancer or CRF clinical trials that were conducted outside of the approved

indications or the current treatment guidelines. Given these reasons, simple frequency tables

without considering the above important variability can be misleading, and hence are not

provided. Instead, findings related to this potential risk in cancer and CRF clinical trials are each

described in the corresponding sections below.

No data from previous cancer and CRF clinical trials indicated decreased survival due to the

administration of EPREX according to the approved indications and treatment guidelines.

The Company is evaluating the impact of epoetin alfa on tumour outcome including PFS and

survival in an appropriately designed clinical trial (Trial EPO-ANE-3010). Trial EPO-ANE-3010

is a randomised, open-label, multicentre, Phase 3 international trial of epoetin alfa plus best

standard supportive care versus standard supportive care alone in anaemic patients with

metastatic breast cancer receiving standard chemotherapy. The trial was conducted in

2,098 anaemic women with metastatic breast cancer, who received first- or second-line

chemotherapy. This was a noninferiority trial designed to rule out a 15% risk increase in tumour

progression or death of epoetin alfa plus standard-of-care as compared with standard-of-care

alone. The trial will end once approximately 1,650 patients have died.

As of the clinical cutoff date of 07 July 2014 for the CSR, the median PFS per investigator

assessment of disease progression was 7.4 months in each arm (HR 1.09, 95% CI: 0.99, 1.20),

indicating the study objective was not met. Median PFS with disease progression assessed by the

Independent Review Committee was 7.6 months in each arm (HR 1.03, 95% CI: 0.92, 1.15). At

clinical cutoff, 1,337 deaths were reported. Median overall survival in the epoetin alfa plus

standard-of-care group was 17.2 months compared with 17.4 months in the standard-of-care

alone group (HR 1.06, 95% CI: 0.95, 1.18).


In the Phase 3 MDS trial (EPOANE3021), 4 (4.7%) patients in the epoetin alfa group and

1 (2.2%) patient in the placebo group had at least 1 treatment-emergent adverse event with onset

during the first 24 weeks, which resulted in death during or after the first 24 weeks. One subject

in each group died due to AML and the other 3 deaths in the epoetin alfa group were due to

sudden death, cachexia, and renal failure.


180

There were 3 more deaths in the epoetin alfa group that were due treatment-emergent adverse

events with onset after the first 24 weeks of the study: 1 death occurred during the 4-week

follow-up period after Week 24, congestive cardiac failure; and 2 deaths occurred due to a

treatment-emergent adverse event with onset during the treatment extension phase: sudden death

and disease progression. However, only 1 out of 45 patients in the placebo arm entered into

extension phase and had follow up after Week 28

The deaths due cachexia, CHF, and disease progression in the epoetin alfa group and AML in the

placebo group all occurred more than 30 days after the last dose of the study drug.

None of the deaths was considered by the investigators to be related to the study drug.


Survival in patients mainly depends on the underlying tumour type, and frequency in the

postmarketing environment is difficult to calculate as limited information is available. Therefore,

the exact frequency for this risk cannot be provided.

Nature of Risk:


The Company has performed comprehensive meta-analyses to evaluate selected clinically

important outcomes, including mortality, in epoetin alfa trials in CKD (dialysis or predialysis).

The Company thoroughly examined the relationship between ESA dose requirements, the

achieved HGB response versus the target HGB level, and clinical outcomes in patients with

CKD (Cardiovascular and Renal Drugs Advisory Committee [CRDAC] 2007). These results

suggest that, while the high HGB-target group demonstrated a higher risk for the primary

composite event endpoint, the risk is predominantly observed for the patients within this group

who exhibited poor ESA response. A similar but somewhat weaker relationship between poor

response and increased risk was also observed in the low HGB-target group.

In a combined analysis of 8 published studies conducted in non-dialysis CKD and 4 published

studies in haemodialysis (CRDAC 2007), the RR for mortality for the higher-HGB target groups

versus the lower-HGB target groups is not significant. For non-dialysis CKD, the RR is

1.01 (95% CI: 0.63, 1.61), and in haemodialysis, the RR is 1.12 (95% CI: 0.91, 1.37).

A meta-analysis reported by Phrommintikul et al included a total of 9 studies: 4 in haemodialysis

and 5 in non-dialysis CKD. The primary finding was a significantly higher risk of all-cause

mortality (risk ratio 1.17 [95% CI: 1.01, 1.35]; p=0.031) in the higher-HGB target group than in

the lower-HGB target group in the fixed-effects model without heterogeneity between studies

(Phrommintikul 2007).

A meta-analysis of the risks of cardiovascular morbidity in patients with CKD treated with ESAs

was conducted (CHMP Response 2014). The following is a brief summary of the Company’s

investigation of epoetin alfa. Data from 27 Company-sponsored trials were pooled to evaluate


181

efficacy or safety of epoetin alfa treatment in adults with CKD. A total of 7,254 patients who

received at least 1 dose of epoetin alfa in the 27 trials were included in the analyses. Twenty of

the 27 trials enroled patients who were not receiving dialysis (N=5,624), and the remaining

7 trials enroled patients who were receiving dialysis (N=1,630). There were 11 correction trials

(designed to correct anaemia with ESA treatment), 8 maintenance trials (designed to maintain

relatively stable levels of HGB with ESA treatment), and 8 other trials. The 27 trials, which were

conducted over a period of 20 years, were never intended to be pooled for analysis. Trial designs,

patient populations, duration of treatment, target HGB concentrations, and other key features

varied considerably from trial to trial. The trials ranged in duration from 8 weeks to up to

3 years. The entry criteria and target levels of HGB varied between trials, with target HGB levels

as high as 14 g/dL in a few trials. The protocol-specified epoetin alfa dose regimens also varied;

some trials had weight-based initial doses while others had fixed initial doses.

The analyses investigating the association between mean achieved HGB (continuous) in the

3-month period prior to an event and the outcomes of interest provided very consistent results

suggesting that higher achieved HGB is associated with a decreased risk of occurrence of

all-cause mortality. The HR for all-cause mortality was 0.721 (95% CI: 0.643, 0.807) for all

patients in the combined studies. This result suggests that, for each 1 g/dL increase in mean

achieved HGB over the 3-month window, the risk of death from any cause decreased by

approximately 28% (1 minus 0.721). The HRs for patients receiving dialysis, patients not

receiving dialysis, patients in the correction studies, and patients in the maintenance studies were

similar to that for all patients.

The analyses investigating the association between cumulative epoetin alfa dose in the 3-month

period prior to an event and the outcomes of interest provided results that, taken as a whole,

suggest an association between higher cumulative epoetin alfa doses and an increased risk of

deaths due to any cause. The HRs of the second-, third-, and fourth- dose quartiles of cumulative

epoetin alfa dose (>3,214 to ≤6,250 IU/wk, >6,250 to ≤10,583 IU/wk, and >10,583 IU/wk)

versus the first quartile (reference category, ≤3,214 IU/wk) were greater than 1 for all-cause

mortality.

Based on the information from the analyses above, the Company concludes that the

HGB concentration in patients should be targeted at between 10 and 12 g/dL, as concentrations

above this range may be associated with increased mortality.

Cancer

A meta-analysis conducted by Amgen, Inc. and the Company of 59 controlled clinical trials

(epoetin alfa and darbepoetin alfa) in CIA has reported data for on-trial deaths or deaths during

long-term follow up (ODAC 2008). Of these 59 trials, a meta-analysis of the data from the

19 trials that reported long-term survival data (≥1 year of follow up) demonstrated an overall

neutral survival risk associated with ESA use, with an OR (ESA versus control) of

1.00 (95% CI: 0.89, 1.12). Data from 8 of the 59 trials have suggested a potential negative effect

of epoetin alfa on survival in patients with cancer. All 8 trials were conducted in treatment

settings not approved for epoetin alfa.


182

The safety signals observed in the trials in question are inconsistent in that some trials reported

potential negative effects during the treatment period (as early as 4 months in

Trial EPO-INT-76), while others reported differences in mortality only after many years of

follow up (Trials 20000161, GOG-191, and a Phase 3 trial of Aranesp in neoadjuvant breast

cancer [PREPARE]).

Overall, these signals have not been consistently observed in individual trials, and meta-analyses

in over 8,000 patients do not indicate a clear effect of epoetin alfa on mortality in the

CIA population. Other controlled trials of ESAs also performed outside of the labelled

indication, but considered to be informative with respect to mortality and/or tumour progression,

have not suggested an increased risk of these events.

If, after 8 weeks, the HGB concentration has increased <1 g/dL (< 0.62 mmol/L) and the

reticulocyte count has increased <40,000 cells/µL above baseline, response is unlikely and

treatment should be discontinued (SmPC Section 4.2).

It is the Company’s position that the data presented by the Company and Amgen Inc. during the

2007 and 2008 meetings of the US Food and Drug Administration (FDA) Oncology Drugs

Advisory Committee (ODAC 2007a, 2007b, 2007c; ODAC 2008) demonstrated no adverse

effect on mortality and survival in patients with cancer receiving chemotherapy and treatment

with ESAs according to product labelling guidelines.

Surgery

Epoetin alfa has been studied in placebo-controlled, double-blind trials of patients scheduled for

major, elective, orthopaedic surgery. Although an increased incidence of DVT in patients

receiving epoetin alfa undergoing surgical orthopaedic procedures has been observed, there is no

evidence of excess mortality observed for the epoetin alfa treatment group.

In a randomised, placebo-controlled trial of epoetin alfa in adults who were undergoing coronary

artery bypass surgery (Annex 4, Trial H87-083), 7 of 126 patients in the epoetin alfa group died

whereas no deaths were reported among the 56 patients in the placebo group. Four of the deaths

occurred during the period of trial drug administration, and all 4 deaths were associated with

TVEs. Perisurgical use of epoetin alfa in patients with severe coronary artery disease is not

recommended and is contraindicated in the SmPC (SmPC Section 4.3).


Not applicable.

Risk Factors:

Cardiovascular deaths account for about 40% of all deaths of patients with CRF, particularly

those on dialysis (Couser 2011).


183

There is some evidence to suggest that lifestyle factors such as obesity and physical inactivity

after cancer diagnosis could contribute to poorer disease outcomes (Wei 2010). Among patients

who have undergone hip surgery, risk factors for early mortality most commonly identified are

increasing age, male gender, and comorbid conditions, especially CVD (Berstock, 2014).


Although the mechanism by which epoetin alfa may affect survival of patients with cancer is not

completely understood, concern exists over the potential for epoetin alfa to directly affect tumour

outcome. It is known that TVEs are under-diagnosed as a proximate cause of death in patients

with cancer. Thus, it is plausible that TVEs could represent a mechanism for increased mortality

associated with epoetin alfa in patients with cancer.

Exploratory analyses of response to epoetin alfa treatment suggest that patients with cancer

failing to achieve a 1 g/dL rise in HGB by 4 or 8 weeks of treatment have higher morbidity and

mortality, although it cannot be determined whether this is due to epoetin alfa treatment or to

inherent differences in the underlying malignancy.

Preventability:

When used according to labelled guidance for correction of anaemia in the setting of CIA

(as well as CRF), there is no evidence that epoetin alfa has an adverse effect on survival.

However, the data strongly suggest that epoetin alfa treatment increases the risk for death and

serious cardiovascular events when administered to a target HGB concentration >12 g/dL.

Patients should be monitored closely to ensure that the lowest approved dose of ESA is used to

provide adequate control of symptoms of anaemia.


Potential increased risk of death.


May lead to increased mortality.

Evidence Source:

Information regarding cancer trials is provided in Annex 4.

Berstock 2014; CHMP Response 2014; Couser 2011; CRDAC 2007; ODAC 2007a, 2007b,

2007c; ODAC 2008; Phrommintikul 2007; Wei 2010

MedDRA Terms:

Survival impact was not collected in clinical trials and therefore there are no preferred terms.


184

Important Potential Risk – Congestive Heart Failure

Frequency (Odds Ratio, 95% Confidence Interval), SAE Outcomes, and Severity of Congestive Heart Failure in Randomised Controlled Clinical Trials, Clinical Trials Without Control, and All Clinical Trials





AE=adverse event; CI=confidence interval; ESA=erythropoiesis-stimulating agent; N/n=number; N/A=not applicablea The stratified Mantel-Haenszel odds ratio (stratified by trial) was used.b Includes EP86-001 (CEO-C01), EP86-00c Includes EPO-CAN-1, EPO-CAN-13, EPO-INT-37, EPO-INT-68, EPO-INT-77, EPO-ITA-2, ZEO-107 (CCP107P108),

ZEO-121 (CC2574P121), ZEO-S01 (CCP102P103)

Chronic Renal Failure – Dialysis Trials: EP86-001 (CEO-C01), EP86-004, EPO-CAN-1, EPO-CAN-13, EPO-INT-37, EPO-INT-68, EPO-INT-77, EPO-ITA-2, ZEO-107 (CCP107P108), ZEO-121 (CC2574P121), ZEO-S01 (CCP102P103)



185











186







187


OEOU21), NON-CISPLATIN (I88-037, OEO-U22 and OEO-U23), AGO/NOGGO (EPO-GER-8), EP92-002, EPO-CAN 15, EPO-CAN-17, EPO-CAN-20, EPO-CAN-203, EPO-CAN-303, EPO-GBR-4, EPO-GBR-7, EPO-GER-20, EPO-GER-22, EPO-GOG-191, EPO-INT-1 (2574-P-416), EPO-INT-10 (EPO-C111-457), EPO-INT-2 (CC2574-P-467), EPO-INT-3 (2574-P-034), EPO-INT-45, EPO-INT-47, EPO-INT-49, EPO-INT-50, EPO-INT-51 (EPO-CA-484), EPO-INT-76 (EPO-CA-489), EPO-J89-040 (J89-040), EPO-N93-004 (N93-004), EPO-P-169 (2574-P-169), EPO-P-174 (CC2574-P-174), MOEBUS, OBE/EPO-INT-03, PR00-03-006, PR00-27-005, PR98-27-008, PR99-11-034/044, PRI/EPO-NED-17, RTOG/PR99-03-046 (PR99-03-046), EPO-CAN-29, EPO-ANE-3010





INDICATION: AUTOLOGOUS BLOOD DONATIONEpoetin alfa (N=402) Non-ESA control (N=242) Odds Ratio a (95% CI)



ABD=autologous blood donation; AE=adverse event; CI=confidence interval; ESA=erythropoiesis-stimulating agent; N/n=number; N/A=not applicablea The stratified Mantel-Haenszel odds ratio (stratified by trial) was used.b Includes CC 2574-P-159, CC 2574-P-165, CC 2574-P-166, H87-017, H87-036, I88-027, I88-058ABD Trials: CC 2574-P-159, CC 2574-P-165, CC 2574-P-166, H87-017, H87-036, I88-027, I88-058



188






AE=adverse event; CI=confidence interval; ESA=erythropoiesis-stimulating agent; N/n=number; N/A=not applicablea The stratified Mantel-Haenszel odds ratio (stratified by trial) was used.b Includes EPO-APO2-474, EPO-INT-34 (EPO-AP02-478), CEO-C04, H87-083, J89-001, M92-011, PR97-19-002 (spine)c Includes N93-057Surgery Trials: EPO-APO2-474, EPO-INT-34 (EPO-AP02-478), CEO-C04, H87-083, J89-001, M92-011, N93-057, PR97-19-002 (spine)



189




7 (6.86%) 6 (11.3%) 0.58 (0.19,1.81)



7 (6.86%) 6 (11.3%)


AE=adverse event; CI=confidence interval; ESA=erythropoiesis-stimulating agent; MDS=myelodysplastic syndrome; N/n=number; N/A=not applicablea The stratified Mantel-Haenszel odds ratio (stratified by trial) was used.b Includes: EPO-ANE-3018 and EPOANE3021MDS Trials: EPO-ANE-3018 and EPOANE3021



The cumulative reporting rate for CHF in the postmarketing setting is 1.9 cases per 100,000 PY

based on 4,575,083 PY of cumulative EPREX exposure through 30 June 2015.


190

Nature of Risk:


Among the 2,046 patients treated in adult haemodialysis trials with EPREX, there were

147 treatment-emergent CHF events. Of those 147 events, 79 (54%) were considered to be

moderate to severe. Forty (27%) of the 147 CHF events were reported as serious adverse events.

Among the 5,610 patients treated in adult predialysis trials with EPREX, there were


moderate to severe. Two hundred sixty-one (30%) of the 857 CHF events were reported as

serious adverse events.

The Company has performed comprehensive meta-analyses to evaluate CHF in epoetin alfa trials

in CKD (dialysis or predialysis).

For Analysis Set I (16 trials in which patients were treated with epoetin alfa, regardless of HGB

target), the CHF rate for predialysis patients treated with epoetin alfa was

4.5% (95% CI: 2.9, 6.7%). In patients receiving dialysis (n=712), the corresponding rate was

2.9% (95% CI: 1.8, 4.6%). For Analysis Set II (meta-analyses of event rates by target HGB

[10 to 12 g/dL or >12 g/dL] from all 19 trials), the CHF rates in predialysis patients treated with

epoetin alfa were 5.7% (95% CI: 3.6, 8.7%) and 3.8% (95% CI: 1.9, 7.7%) in the 10 to 12 g/dL

and >12 g/dL groups, respectively. In patients receiving dialysis, the corresponding rates were

3.0% (95% CI: 1.8, 4.9%) and 2.3% (95% CI: 0.6, 8.7%) in the 10 to 12 g/dL and >12 g/dL

groups, respectively. For Analysis Set III (meta-analyses of event rates by target HGB

[10 to 12 g/dL or >12 g/dL] from 6 trials randomised by high- and low-HGB targets), the OR in

predialysis patients treated with epoetin alfa was 1.45 (95% CI: 1.05, 2.01) for the

>12-g/dL group versus the 10- to 12-g/dL group. No formal statistical analysis was conducted

for patients receiving dialysis as there was only 1 event in the >12 g/dL group and no events in

the 10- to 12-g/dL group.

The MAH conducted a more recent meta-analysis of the safety of epoetins on patients with CKD

(CHMP Response 2014). The analyses investigating the association between mean achieved

HGB (continuous) in the 3-month period prior to an event provided very consistent results

suggesting that higher achieved HGB is associated with a decreased risk of occurrence of

cardiovascular events (a composite of events that included heart failure). The HR for

cardiovascular events was 0.854 (95% CI: 0.763, 0.955) for all patients in the combined trials.

This result suggests that, for each 1 g/dL increase in mean achieved HGB over the 3-month

window, the risk of cardiovascular events decreased by approximately 15%. The HRs for

patients receiving dialysis, patients not receiving dialysis, patients in the correction trials, and

patients in the maintenance trials were similar to that for all patients.

The analyses investigating the association between cumulative epoetin alfa dose in the 3-month

period prior to an event provided results that, taken as a whole, suggest an association between

higher cumulative epoetin alfa doses and an increased risk of deaths due to cardiovascular events

(a composite of events that included heart failure). However, causality cannot be ascertained, the


191

associations were not uniformly consistent in all analyses, and there was no clear dose-dependent

increase. The HRs of the second-, third-, and fourth-- dose quartiles of cumulative epoetin alfa

dose (>3,214 to ≤6,250 IU/wk, >6,250 to ≤10,583 IU/wk, and >10,583 IU/wk) versus the first

quartile (reference category, ≤3,214 IU/wk) were greater than 1 for cardiovascular events.

Cancer

Among the 5,827 adult patients treated in cancer trials with EPREX, there were


Grade 2 and 52 (12%) were considered to be Grade 3. Thirty-three (7%) of the 443 CHF events

were reported as serious adverse events.


Among the 402 adult patients treated in orthopaedic surgery clinical trials with EPREX, there

were 6 treatment-emergent CHF events. Of those 6 events, 1 (16.7%) was considered to be

moderate or severe. There were no reports of CHF as serious adverse events in EPREX-treated

ABD patients.

Surgery

Among the 1,352 adult patients treated in orthopaedic surgery clinical trials with EPREX, there

were 102 treatment-emergent CHF events. Of those 102 events, 36 (35%) were considered to be

moderate to severe. There were no reports of CHF as serious adverse events in EPREX-treated

surgical patients.


Among the 102 adult patients treated in the MDS clinical trials with EPREX, there were

7 treatment-emergent CHF events. Of those 7 events, 3 events were Grade 1, 2 events were

Grade 2, and 2 events were Grade 3. Two (29%) of the CHF events were reported as serious

adverse events.



According to 1 review, the prevalence of heart failure is about 37% among patients upon starting

dialysis (Lisowska 2004). Another review (Schiffrin 2007) summarised the cardiovascular risk

by CKD stage. Specifically, risk estimates of cardiovascular risk were 1.5 for CKD Stage 2,

ranged from 2 to 4 for Stage 3, ranged from 4 to 10 for Stage 4, and ranged from 10 to 50 for

Stage 5. The younger the person, higher the RR compared with people who did not have CKD.

Cancer

A nationwide study in Sweden observed a 70% greater overall incidence of coronary heart

disease in patients with cancer compared with the general population without cancer. The IR was

highest for leukaemia and cancers of the small intestine, kidney, lung, and liver during the first

6 months of diagnosis (Zöller 2012). Reviews have also reported on incidence of different types

of cardiovascular morbidity (such as CHF) in relation to specific antineoplastic drugs


192

(Senkus 2011; Khakoo 2008). Prevalence of comorbid CVD has been reported separately for

specific cancer types in different studies. For instance, according to a US Medicare study of

patients with breast cancer aged 66 years and older, the prevalence of CVD at the time of cancer

diagnosis was 12.8% (Patnaik 2011). In a hospital-based study in Italy, of the 189 patients who

underwent surgery for non-small cell lung cancer, 17.5% had concurrent CVD (Pavia 2007). A

high prevalence of cardiovascular comorbidity of 52% has been observed among patients with

metastatic colorectal cancer (Overbeek 2012). In another study of 5,077 patients with prostate

cancer in the United States, 256 patients had CHF or MI at baseline (Nanda 2009).

Surgery

In a US population-based study of patients with hip fractures, the prevalence of preoperative

heart failure was 27% and rates of postoperative heart failure were 6.7% at 7 days and 21.3% at

1 year (Cullen 2011). Results from a US nationwide inpatient survey of cases of elective bilateral

knee arthroplasty found the complications-weighted prevalence of CHF to be 11.8%

(Memtsoudis 2011).


A cohort of 840 MDS patients in an Italian study reported that cardiac disease was the most

frequently observed (25%) comorbidity. The frequency of CHF or ejection fraction <50% was

19% (Della Porta, 2011). In a US study of 52 elderly MDS patients, the prevalence of CHF was

48.2% (Goldberg, 2010).

Risk Factors:

Known risk factors for CHF are hypertension, diabetes, coronary artery disease, heart attack,

certain diabetes medications, certain anticancer treatments and chemotherapy medications,

radiation therapy applied to the heart area, sleep apnoea, congenital heart defects, viruses,

alcohol use, and irregular heartbeats (Mayo Clinic, 2015: heart failure; Mayo Clinic, 2015:

cancer).


In CHF, an increase in HGB concentration is associated with a reduction in ejection fraction and

an increase in blood pressure.

Inflammation and associated oxidative stress interact with erythropoiesis at several levels.

Pro-inflammatory cytokines and inflammatory mediators suppress native erythropoietin

production and blunt response to erythropoietin at the receptor level. Patients with CKD with the

combination of wasting and inflammation are most likely to have more severe anaemia and to be

hyporesponsive to epoetin alfa. Congestive heart failure is associated with elevated levels of

pro-inflammatory cytokines, which may contribute to wasting and anaemia (Bárány 2007).

Preventability:

The recommended desired HGB concentration range is between 10 g/dL to 12 g/dL

(6.2 to 7.5 mmol/l). EPREX should be administered in order to increase HGB to not greater than


193

12 g/dL (7.5 mmol/l). A rise in HGB of greater than 2 g/dL (1.25 mmol/l) over a 4-week period

or a sustained HGB level of greater than 12 g/dL (7.5 mmol/l) should be avoided.

Haemoglobin concentrations should be monitored closely to ensure that the lowest approved

dose of EPREX is used to provide adequate control of anaemia while maximising the patients’

safety.


Potential for increased morbidity and mortality.


The potential public health impact of CHF related to EPREX treatment is unknown.

Evidence Source:

Information regarding clinical trials is provided in Annex 4.


30 June 2015.

Bárány 2007; CHMP Response 2014; Cullen 2011; Della Porta 2011; Goldberg 2010;

Khakoo 2008; Lisowska 2004; Mayo Clinic, 2015: cancer; Mayo Clinic, 2015: heart failure;

Memtsoudis 2011; Nanda 2009; Overbeek 2012; Patnaik 2011; Pavia 2007; Schiffrin 2007;

Senkus 2011; Zöller 2012

MedDRA Terms:

Cardiac Failure SMQ; scope=narrow and broad


194

SVII.4. Identified and Potential Interactions

SVII.4.1. Overview of Potential for Interactions

Epoetin alfa increases RBC maturation and RBC count in animals and humans. Although no

formal drug interaction studies have been conducted with epoetin alfa and drugs that affect

erythropoiesis, caution should be exercised in the concomitant use of drugs known to affect

erythropoiesis because they may impact the response to epoetin alfa, such as an increase in the

number of erythrocytes, HGB values, reticulocyte counts, and iron-incorporation rate.

There is no evidence indicating that treatment with epoetin alfa alters the metabolism of other

drugs. However, because cyclosporine is bound by RBCs, there is potential for decreased serum

levels of cyclosporine when used with epoetin alfa. The SmPC addresses the need to monitor

blood levels of cyclosporine and adjust cyclosporine dose as necessary when cyclosporine is

given concomitantly with epoetin alfa (SmPC Section 4.5).

A drug interaction trial (Trial EPO-PHI-383) was conducted in women with metastatic breast

cancer to evaluate the effect of a single 40,000-IU SC dose of EPREX on the steady-state

pharmacokinetic parameters of trastuzumab (6 mg/kg every 3 weeks). The trial demonstrated

that co-administration of EPREX had no effect on the pharmacokinetics of trastuzumab

(EPREX IB 2012).

Detailed metabolic degradation studies with EPREX have not been conducted, and the major

routes of elimination have not been determined. However, measurement of epoetin alfa

following IV administration demonstrated 10% excretion by the kidneys. In normal volunteers,

the half-life of IV-administered EPREX is approximately 20% shorter than the half-life in

patients with CRF. Therefore, caution should be exercised in the concomitant use of EPREX

with drugs that are known to interfere with renal function.

The safety and optimal dosage regimen of EPREX have not been established in the presence of

hepatic dysfunction. However, due to decreased metabolism, patients with hepatic dysfunction

may have increased erythropoiesis with EPREX. Therefore, EPREX should also be used with

caution in patients with chronic liver failure.

To date, there are no identified important interactions with medicinal products, food, herbs, and

other substances.


195

SVII.4.2. Important Identified and Potential Interactions

CyclosporinEffect of interaction Concomitant use of epoetin alfa with cyclosporin theoretically could

decrease serum cyclosporin levels and, therefore, increase the risk of renal transplant rejection.

Evidence source Freeman, 1991

Possible mechanisms Epoetin alfa increases RBC maturation, thereby increasing RBC count. Because cyclosporin binds to RBCs, there is a resultant potential for decreased serum levels of cyclosporin when used with epoetin alfa.

Potential health risk Increased risk of renal transplant rejectionMedDRA preferred terms: drug interaction, acute graft versus host disease, graft versus host disease, kidney transplant rejection, transplant rejection

Discussion Although there is a theoretical risk for a drug interaction with cyclosporin, an actual risk has not been identified.

MedDRA=Medical Dictionary for Regulatory Activities; RBC=red blood cell

SVII.5. Pharmacologic Class Effects

Established risks with other ESAs that are considered to be important identified or potential risks

with EPREX include:

Thrombotic vascular events



Disease progression

Survival impact

Risks that are considered to be pharmacologic class effects and are also important identified or

potential risks with EPREX are characterised in Module SVII.3; the frequencies of these risks

seen with the EPREX compared with those seen with other products in the same or similar

pharmacologic class are presented in Module SVII.5.1


196

SVII.5.1. Pharmacologic Class Risks Already Included as Important Identified or Potential Risks

Frequency:Risk(MedDRA preferred term) In Clinical Trials of EPREX*

With Other Products in Same ClassSource of data / journal reference: SmPC†

Thrombotic Vascular Events An increased incidence of thromboembolic events (including the following terms listed in Section 4.8 of the SmPC: arterial and venous, fatal and non-fatal events, such as DVT, pulmonary emboli, retinal thrombosis, arterial thrombosis (including MI), cerebrovascular accidents, (including cerebral infarction and cerebral haemorrhage),transient ischaemic attacks, and shunt thrombosis (including dialysis equipment),and thrombosis within arteriovenous shunt aneurisms) has been reported in patients receiving ESAs, including epoetin alfa (SmPC Sections 4.4 and 4.8).Frequency is considered “common” (≥1/100 to <1/10 cases per patient) as stated in Section 4.8 of the SmPC.

Aranesp:Thromboembolic events (Uncommon for patients with CRF, common for patients with cancer)

Binocrit:Same language as EPREX

Eporatio:Thromboembolic events(Not known)

NeoRecormon:Thromboembolic events(Common for patients with cancer)

Silapo:An increased incidence of thromboembolic events has been observed in patients receiving erythropoietic agents

Pure Red Cell Aplasia Antibody-mediated PRCA has been very rarely reported in <1/10,000 cases per PYafter months to years of treatment with EPREX (SmPC Section 4.8).

Aranesp:PRCA (Not known-isolated cases reported)

Binocrit:PRCA (Not known)

Eporatio:PRCA (isolated cases)

NeoRecormon:(isolated cases)

Silapo:(Frequency not known-cases have been very rarely reported in patients with CRF)


197




Hypertension is considered “common” (≥1/100 to <1/10 cases per patient) as stated in Section 4.8 of the SmPC.Hypertensive crisis with encephaolopathy and seizures, requiring immediate attention of a physician and intensive medical care, have occurred during epoetin alfa treatment in patients with previously normal or low blood pressure (SmPC Sections 4.4 and 4.8).

Aranesp:Hypertension (very common)

Binocrit:Hypertension (common)

Eporatio:Hypertension (common)

NeoRecormon:Hypertension (common)

Silapo:Hypertension may occur in epoetin alfa-treated patients. The most frequent adverse reaction during treatment with epoetin alfa is a dose-dependent increase in blood pressure or aggravation of existing hypertension

Disease Progression In controlled clinical trials, use of EPREX, ERYPO, and other ESAs have demonstratedshortened overall survival and increased deaths attributed to disease progression at 4 months in patients with metastatic breast cancer receiving chemotherapy when administered to target a HGB of 12 to 14 g/dL (7.5 to 8.7 mmol/l) (SmPC Section 4.4).Decreased locoregional control in patients with advanced head and neck cancer receiving radiation therapy when administered to achieve a HGB concentration level of greater than 14 g/dL (8.7 mmol/l) has also been observed (SmPC Section 4.4).

Aranesp:Same language as EPREX


Eporatio:Same language as EPREX

NeoRecormon:Same language as EPREX

Silapo:Same as language EPREX


198



Survival Impact In controlled clinical trials, use of EPREX, ERYPO, and other ESAs increased the risk of death when administered to achieve a HGB concentration of 12 g/dL (7.5 mmol/L) in patients with active malignant disease receiving neither chemotherapy nor radiation therapy.Shortened overall survival and increased deaths attributed to disease progression at 4 months in patients with metastatic breast cancer receiving chemotherapy when administered to achieve a HGB concentration range of 12 to 14 g/dL (7.5 to 8.7 mmol/L) has also been observed (SmPC Section 4.4).Erythropoiesis-stimulating agents are not indicated for use in this patient population.

Aranesp:Same language as EPREX


Eporatio:Same language as EPREX

NeoRecormon:Same language as EPREX

Silapo:Same language as EPREX

ADR=adverse drug reaction; CKD=chronic kidney disease; CNS=central nervous system; CRF=chronic renal failure; DVT=deep venous thrombosis; ESA=erythropoiesis-stimulating agent; HGB=haemoglobin; MedDRA=Medical Dictionary for Regulatory Activities; MI=myocardial infarction; PRCA=pure red cell aplasia; PY=patient years; SmPC=Summary of Product Characteristics* Incidence of ADRs† Aranesp SmPC 2013, Binocrit SmPC 2013, Eporatio SmPC 2013, NeoRecormon 2012, Silapo 2012


199

SVII.5.2. Important Pharmacologic Class Effects That Are NOT Considered to be Important Identified or Potential Risks

There are no important pharmacologic class effects that are not considered to be important

identified or potential risks with EPREX.


200



Module SVIII: Summary of the Safety Concerns











201

Summary of Safety Concerns

Important identified risks Thrombotic vascular events



Important potential risks Disease progression

Survival impact


Missing information None


202


PART III: PHARMACOVIGILANCE PLAN











203

The pharmacovigilance actions planned in response to each safety concern are summarised in the

following table.

III.1. Safety Concerns and Overview of Planned Pharmacovigilance Actions

Safety ConcernAreas requiring confirmation or further investigation

Proposed routine and additional pharmacovigilance activities Objectives

Important Identified RisksThrombotic Vascular Events

1. Monitor reporting rates

2. Evaluate risk factors

Ongoing monitoring with routine pharmacovigilance activities

Additional: Trial EPO-ANE-3010

Routine evaluation of the risk

Evaluate the incidence of TVEs in a randomised, open-label, multicentre,Phase 3 trial of EPREX plus standard supportive care versus standard supportive care alone in anaemicpatients with metastatic breast cancer receiving standard chemotherapy

Pure Red Cell Aplasia

1. Monitor reporting rates



Additional: SemiannualImmunogenicity Report; Independent Safety Advisory Committee adjudication (ISAC); PRCA pharmacovigilance plan

Routine monitoring of the risk

Estimate the incidence of anti-human erythropoietin Ab and anti-erythropoietin PRCA in patients with SC exposure to ESAs

Hypertension/Hypertensive crisis1. Monitor reporting rates




Important Potential RisksDisease Progression1. Monitor reporting rates





Evaluate the occurrence of disease progression in a randomised, open-label, multicentre, Phase 3 trial of EPREX plus standard supportive care versus standard supportive care alone in anaemic patients with metastatic breast cancer receiving standard chemotherapy

Survival Impact1. Monitor reporting rates





Evaluate the survival impact in a randomised, open-label, multicentre, Phase 3 trial of EPREX plus standard supportive care versus standard supportive care alone in anaemic patients with metastatic breast cancer receiving standard chemotherapy

Congestive Heart Failure1. Monitor reporting rates





204

Safety ConcernAreas requiring confirmation or further investigation

Proposed routine and additional pharmacovigilance activities Objectives

Ab=antibody; ESA=erythropoiesis-stimulating agent; PRCA=pure red cell aplasia; SC=subcutaneous; TVE=thrombotic vascular event

III.2. Additional Pharmacovigilance Activities to Assess the Effectiveness of Risk Minimisation Measures

There are no additional pharmacovigilance activities being performed specifically to measure the

effectiveness of the risk minimisation measures for EPREX.

III.3. Studies and Other Activities Completed Since the Last Update of the Pharmacovigilance Plan

A CSR for Trial EPO-ANE-3010 has been completed given that the number of PFS events

reached the target of 1,650 events for the analysis of the primary endpoint. A final analysis for

survival will be performed after 1,650 patients have died. As of the clinical cutoff date of

07 July 2014 for the CSR, 1,337 deaths have been reported.


205

III.4. Details of Outstanding Additional Pharmacovigilance Activities

III.4.1. Imposed Mandatory Additional Pharmacovigilance Activity(Key to Benefit-Risk)

No imposed mandatory additional pharmacovigilance activities are planned or ongoing for

EPREX.

III.4.2. Mandatory Additional Pharmacovigilance Activity(Being a Specific Obligation)

No mandatory additional pharmacovigilance activities are planned or ongoing for EPREX.

III.4.3. Required Additional Pharmacovigilance Activities to Address Specific Safety Concerns or to Measure Effectiveness of Risk Minimisation Measures

Required Additional Pharmacovigilance Activities

Description of activity(or study title if known) Milestone(s) Due Date(s)

1. Trial EPO-ANE-3010 (A Randomised, Open-Label, Multicentre, Phase 3 Study of Epoetin Alfa Plus Standard Supportive Care Versus Standard Supportive Care in Anemic Patients With Metastatic Breast Cancer Receiving Standard Chemotherapy)

Final report for OS

4Q 2017

OS=overall survival.

III.4.4. Stated Additional Pharmacovigilance Activities

No stated additional pharmacovigilance activities are planned or ongoing for EPREX.


206

III.5. Summary of the Pharmacovigilance Plan

III.5.1. Table of Ongoing and Planned Additional Pharmacovigilance Studies/Activities in the Pharmacovigilance Plan

Study ID/activity type, title and category (1-3) Objectives

Safety concerns addressed

Status (planned, started)

Date for submission of interim or final reports (planned or actual)

Trial EPO-ANE-3010

Randomised, Open-Label, Multicentre, Phase 3 Study of Epoetin Alfa Plus Standard Supportive Care Versus Standard Supportive Care in Anemic Patients With Metastatic Breast Cancer Receiving Standard Chemotherapy

Category 3

Assess the impact on tumour progressionand TVEs, in terms of PFS, of EPREX plus standard-of-care compared with standard-of-care alone (packed RBC transfusions), when used to treat anaemia in patients with metastatic breast cancer receiving first-line or second-line chemotherapy.

Disease progression; TVEs, survival impact

Ongoing Final report for OS in 4Q 2017

OS=overall survival; PFS=progression-free survival; RBC=red blood cell; TVE=thrombotic vascular event.


207

III.5.2. Table of Completed Studies/Activities From the Pharmacovigilance Plan

Study ID/Protocol(activity type, title and category

[1-3]) Objectives Safety concerns addressed Status

Date of submission of interim or final study report

Trial EPO-ANE-4014

Prospective, Immunogenicity Surveillance Registry to Estimate the Incidence of Erythropoietin Antibody-Mediated Pure Red Cell Aplasia Among Subjects With Chronic Renal Failure and Subcutaneous Exposure to Recombinant Erythropoietin Products

Category 2

Estimate IR of erythropoietinAb-mediated PRCA with SC exposure to PS-80 formulation of EPREX and compare with that of other currently marketed ESAs with adjustment for duration of exposure

PRCA Completed Final study report submitted

25 Jan 2012

Trial EPO-ANE-4008

A randomised, open-label, multicentre study evaluating thrombovascular events in subjects with cancer receiving chemotherapy and administered epoetin alfa once or 3 times a week for the treatment of anaemia

Category 2

Further evaluate the safety profile of the QWdosing regimen in patients with cancer, with particular focus on the incidence of TVEs

TVEs Completed Final study report submitted 31 Mar 2010

Trial EPOANE4076a

A Prospective, Immunogenicity Surveillance Registry of Erythropoiesis-Stimulating Agents with Subcutaneous Exposure in Thailand

Category 3

Estimate the incidence of anti-human erythropoiesis and anti-erythropoietin PRCA in patients using any ESA by the SC route.

PRCA Completed Final report submitted 05 May 2015

Ab=antibody; ESA=erythropoiesis-stimulating agent; IR=incidence rate; MAH=market authorisation holder; PRCA=pure red cell aplasia; PRIMS=Pharmacoepidemiology Registry EPO-ANE-4014 Prospective Immunogenicity Surveillance; PS-80=polysorbate-80; QW=once weekly; SC=subcutaneous; TVE=thrombotic vascular event

aTrial EPOANE4076 was being conducted by the collaboration among Nephrology Society of Thailand, the Thai Society of Haematology, the Association of Hospital Pharmacy (Thailand), and the Adverse Product Reaction Monitoring Center of the Food and Drug Administration Thailand, and not by the MAH. The final report was prepared by the principal investigator.


208

European Union Risk Management Plan (EU-RMP)

EPREX (epoetin alfa)

PART IV: PLANS FOR POSTAUTHORISATION EFFICACY STUDIES











209

IV.1 Applicability of Efficacy to All Patients in the Target Population

EPREX has been approved in numerous countries worldwide for the treatment of anaemia in

patients with CRF (on dialysis and predialysis) and anaemia and reduction of transfusion

requirements in adult patients with cancer receiving chemotherapy. It has also been approved in

several countries as a facilitator of autologous blood predonation and to reduce allogeneic blood

requirements in the perisurgical setting. The first approval, in 1988, was in the CRF setting. Over

the course of the clinical development programme, the efficacy of EPREX has been studied in

15,339 patients in clinical trials with over 94,000 person-months of exposure. Over 200 patients

have been treated in clinical trials for ≥24 months and thus, the long-term efficacy of EPREX has

been well documented.

Forty-two percent of patients in the clinical trials were aged 65 years or older and 17% were

aged 75 years or older. However, epoetin alfa has been shown to be efficacious in the paediatric

populations for CRF (dialysis) and CIA, and there is no mention of age-related effects on

efficacy in the SmPC.

A majority of patients (69%) were White, while 13% were Black and 9% were Asian, Hispanic,

or of a mixed race (data on ethnic and racial origin were missing for 10% of patients). The

efficacy and safety of EPREX in clinical trials has led to its approval in multiple Latin American

and Asian countries; therefore, there is no reason to suggest differences in the efficacy of

EPREX in any particular ethnic or racial subgroup.

IV.2. Tables of Postauthorisation Efficacy Studies

There are no postauthorisation efficacy trials planned or currently ongoing with the use of

EPREX.

IV.3. Summary of the Postauthorisation Efficacy Development Plan

There are no postauthorisation efficacy trials planned or currently ongoing with the use of

EPREX.

IV.4. Summary of Completed Postauthorisation Efficacy Studies

No efficacy studies were required postauthorisation.


210



PART V: RISK MINIMISATION MEASURES











211

V.1. Risk Minimisation Measures by Safety Concern

The Company has not identified any risk minimisation activities needed beyond those already

outlined in the current SmPC. The Company continues its ongoing pharmacovigilance and will

assess the need for any risk minimisation actions as new data emerges.


Safety Concern 1: Thrombotic vascular events

Objective(s) of the risk minimisation measures

Advise regarding the risk of TVEs and provide guidance on ways to minimise the risk of TVEs.

Routine risk minimisation measures

The increased risk of TVEs is described in Sections 4.4 and 4.8 of the SmPC.

For patients with cancer, EPREX should be administered by the SC route with dose adjustments to maintain HGB concentrations between 10 to 12g/dL. Section 4.2 of the SmPC provides guidance for appropriate dose adjustment when HGB values exceed 12 g/dL and to ensure that the lowest approved dose is used.

EPREX is contraindicated in surgery patients who cannot receive such prophylaxis (SmPC Section 4.3). Thrombosis prophylaxis is recommended in high-risk patients (SmPC Section 4.4). EPREX is not recommended in perisurgery patients with a baseline HGB >13 g/dL(SmPC Section 4.4). Section 4.4 of the SmPC advises that HGB levels should be closely monitored due to a potential increased risk of TVEs and fatal outcomes when patients are treated at above-target HGBlevels.

An increased incidence of TVEs has been observed in patients receiving ESAs (SmPC Section 4.8); this risk should be weighed against the benefit from treatment with EPREX, particularly in patients at increased risk of TVEs, such as obese patients and patients with a prior history of TVEs (eg, DVT or pulmonary embolism) (SmPC Section 4.4).

Additional risk minimisation measure(s)

Based on the risk assessment, the MAH believes the language included in the SmPC, along with the Pharmacovigilance Plan are sufficient tools to manage the risk for patients treated with EPREX. Therefore, no additional risk minimisation activities are proposed.

Effectiveness of risk minimisation measures

How effectiveness of risk minimisation measures for the safety concern will be measured

Spontaneous and literature reports review

Criteria for judging the success of the proposed risk minimisation measures

Stable reporting trend analysis of postmarketing data

Planned dates for assessment At the end of each PBRER/PSUR reporting interval.

Results of effectiveness measurement

Stable reporting observed

Impact of risk minimisation Achieving aim of stable reporting in postmarketing surveillance


212

Comment The MAH will continue to monitor TVEs.

Safety Concern 2: Pure Red Cell Aplasia


Advise regarding the risk of PRCA and provide guidance on ways to minimise the risk of PRCA.


Intravenous administration should be used when possible. Where IV access is not readily available, EPREX may be administered subcutaneously (SmPC Section 4.2).

The use of EPREX is contraindicated in patients who develop PRCA following treatment with any ESA (SmPC Section 4.3). Physicians are advised of the incidence of PRCA and measures that can be taken to diagnose PRCA in Sections 4.4 and 4.8 of the SmPC.

In patients developing sudden lack of efficacy defined by a decrease in HGB (1 to 2 g/dL per month) with increased need for transfusions, a reticulocyte count should be obtained and typical causes of non-response (eg, iron, folate or vitamin B12 deficiency, aluminium intoxication, infection or inflammation, blood loss and haemolysis) should be investigated. (See Section 4.4 of the SmPC).








Planned dates for assessment At the end of each PBRER/PSUR reporting interval



Impact of risk minimisation Achieving aim of stable reporting of erythropoietin Ab-mediated PRCA in postmarketing surveillance

Comment The MAH will continue to monitor PRCA.


213

Safety Concern 3: Hypertension/Hypertensive crisis


Advise regarding the risk of hypertension and provide guidance on ways to minimise the risk of hypertension.


The use of EPREX is contraindicated in patients with uncontrolled hypertension (SmPC Section 4.3).

Sections 4.4 and 4.8 of the SmPC state that blood pressure should be closely monitored and controlled as necessary. Epoetin alfa should be used with caution in the presence of untreated, inadequately treated, or poorly controllable hypertension. It may be necessary to add or increase antihypertensive treatment. If blood pressure cannot be controlled, epoetin alfa treatment should be discontinued(SmPC Section 4.4).

Hypertensive crisis with encephalopathy and seizures, requiring the immediate attention of a physician and intensive medical care, have occurred also during epoetin alfa treatment in patients with previously normal or low blood pressure. Particular attention should be paid to sudden stabbing migraine-like headaches as a possible warning signal(see SmPC Sections 4.4 and 4.8).












Comment The MAH will continue to monitor hypertension.


214


Safety Concern 4: Disease Progression


Advise regarding the risk of disease progression and provide guidance on ways to minimise the risk of disease progression.


Section 4.4 of the SmPC addresses the potential for tumour growth progression with the administration of ESAs and demonstrated increased mortality in patients with head and neck cancer and breast cancer when administered to target a HGB concentration of 12 to 14 g/dL (7.5 to 8.7 mmol/L).

When used according to labelled guidance for correction of anaemia in the setting of CIA, there is no evidence that epoetin alfa has an adverse effect on disease progression. The SmPC only indicates treatment in those patients receiving concomitant chemotherapy, and as such, is not indicated in patients with cancer-induced anaemia who are not receiving concomitant chemotherapy, or are receiving radiotherapy only.

Epoetin alfa should be discontinued in non-responding patients(SmPC Section 4.2).












Comment The MAH will continue to monitor disease progression.


215

Safety Concern 5: Survival Impact


Advise regarding the risk of impact on survival and provide guidance on ways to minimise the risk of death.


Sections 4.4 and 5.1 of the SmPC address the risk of survival impact.

When used according to labelled guidance for correction of anaemia in the setting of CIA, there is no evidence that epoetin alfa has an adverse effect on survival. However, the data strongly suggest that epoetin alfa treatment increases the risk of death and serious cardiovascular events when administered to target HGB >12 g/dL(SmPC Section 4.4). The SmPC advises that the target HGB should be up to 12 g/dL. Dose adjustments should be made to maintain HGBconcentrations between 10 to 12g/dL. A sustained HGB level of greater than 12g/dL should be avoided; guidance for appropriate dose adjustment for when HGB values exceed 12 g/dL is also described in Section 4.2 of the SmPC.

Patients should be monitored closely to ensure that the lowest approved dose of ESA is used to provide adequate control of symptoms of anaemia.

In order to prevent HGB concentration from exceeding the recommended target (12 g/dL) or rising too rapidly (greater than 1 g/dL in 2 weeks), the guidelines for dose and frequency of dose adjustments should be followed (SmPC Section 4.2).












Comment The MAH will continue to monitor survival impact.


216

Safety Concern 6: Congestive Heart Failure


Advise regarding the risk of CHF and provide guidance on ways to minimise the risk of CHF.


The target HGB should be up to 12 g/dL and should not be exceeded (SmPC Section 4.4). Physicians are also warned that HGB levels greater than 12 g/dL may be associated with a higher risk of cardiovascular events in patients with CRF (SmPC Section 4.4).












Comment The MAH will continue to monitor CHF.

Ab=antibody; CHF=congestive heart failure; CIA=chemotherapy-induced anaemia; CNS=central nervous system; CRF=chronic renal failure; DVT=deep vein thrombosis; ESA=erythropoiesis-stimulating agent; HGB=haemoglobin; IV=intravenous; MAH=marketing authorisation holder; PRCA=pure red cell aplasia; PBRER/PSUR=Periodic Benefit Risk Evaluation Report/Periodic Safety Update Report; SC=subcutaneous; SmPC=Summary of Product Characteristics; TVE=thrombotic vascular event


217

V.2. Risk Minimisation Measure Failure

No risk minimisation measure has been judged to have failed to date.

V.3. Summary Table of Risk Minimisation Measures

Safety ConcernRoutineRisk Minimisation Measures

Additional Risk Minimisation Measures

Important identified risks:

Thrombotic vascular events The increased risk of TVEs is described in SmPC Sections 4.4 and 4.8.

Patients with cancer being treated for CIA should be monitored closely to ensure that the lowest approved dose of ESA is used to provide adequate control of symptoms of anaemia. Haemoglobin values should not be allowed to rise above 12 g/dL (SmPC Sections 4.2 and 4.4).

Thrombosis prophylaxis for TVEs in high-risk patientsis also recommended (SmPC Section 4.4) and EPREX is contraindicated in surgery patients who for any reason cannot receive antithrombotic prophylaxis (SmPC Section 4.3). The use of EPREX is also not recommended in perisurgery patients with a baselineHGB >13 g/dL (SmPC Section 4.4).

None

Pure red cell aplasia Intravenous administration should be used when possible. Where IV access is not readily available, EPREX may be administered subcutaneously (SmPC Section 4.2).

Physicians are advised of the incidence of PRCA and measures that can be taken to diagnose PRCA, as stated in Sections 4.4 and 4.8 of the SmPC. The use of EPREX is contraindicated in patients who develop PRCA following treatment with any ESA (SmPC Section 4.3).

None


The use of EPREX is contraindicated in patients with uncontrolled hypertension (SmPC Section 4.3). Blood pressure should be closely monitored and controlled as necessary (SmPC Sections 4.4 and 4.8). EPREX should be used with caution in the presence of untreated, inadequately treated or poorly controllable hypertension. It may be necessary to add or increase antihypertensive treatment. If blood pressure cannot be controlled, EPREX treatment should be discontinued (SmPC Section 4.4).

None


218

Safety ConcernRoutineRisk Minimisation Measures


Important potential risks:

Disease progression When used according to labelled guidance for correction of anaemia in the setting of CIA, there is no evidence that epoetin alfa has an adverse effect on disease progression. However, the data suggest that ESA treatment may increase mortality in patients with head and neck cancer and breast cancer when administered to a target HGB concentration of 12 to 14 g/dL (SmPC Section 4.4). Epoetin alfa should be discontinued in non-responding patients (SmPC Section 4.2).

None

Survival impact When used according to labelled guidance for correction of anaemia in the setting of CIA, there is no evidence that epoetin alfa has an adverse effect on survival. However, the data suggest that epoetin alfa treatment increases the risk of death and serious cardiovascular events when administered to a target HGB concentration >12 g/dL (SmPC Sections 4.4 and 5.1); therefore, the target HGB concentration of 12 g/dL should not to be exceeded (SmPC Section 4.4). Patients should be monitored closely to ensure that the lowest approved dose of ESA is used to provide adequate control of symptoms of anaemia.Guidelines for dose and frequency of dose adjustments should be followed (SmPC Section 4.2)

None

Congestive heart failure The target HGB should be up to 12 g/dL and should not be exceeded. Haemoglobin concentrations >12 g/dL may be associated with a higher risk of cardiovascular events in patients with CRF (SmPC Section 4.4).

None

CIA=chemotherapy-induced anaemia; CNS=central nervous system; CRF=chronic renal failure; ESA=erythropoiesis-stimulating agent; HGB=haemoglobin; IV=intravenous; PRCA=pure red cell aplasia; SmPC=Summary of Product Characteristics; TVE=thrombotic vascular events


219



PART VI: SUMMARY OF ACTIVITIES IN THE RISK MANAGEMENT PLAN BY PRODUCT











220

VI.1. Elements for Summary Tables in the EPAR

VI.1.1. Summary Table of Safety Concerns

Important identified risks Thrombotic vascular events



Important potential risks Disease progression

Survival impact


Missing information None

VI.1.2. Table of Ongoing and Planned Additional Pharmacovigilance Studies/Activities in the Pharmacovigilance Plan

Study/activity type, title and category (1-3) Objectives

Safety concerns addressed


Date for submission of interim or final reports (planned or actual)

Trial EPO-ANE-3010

Randomised, Open-Label, Multicentre, Phase 3 Study of Epoetin Alfa Plus Standard Supportive Care Versus Standard Supportive Care in Anaemic Patients With Metastatic Breast Cancer Receiving Standard Chemotherapy

Category 3

Assess the impact on tumour progression and TVEs, in terms of PFS, of EPREX plus standard-of-carecompared with standard-of-care alone (packed RBC transfusions), when used to treat anaemia in patients with metastatic breast cancer receiving first-line or second-line chemotherapy

Disease progression; TVE, survival impact

Ongoing Final report for OS in 4Q 2017

MAH=market authorisation holder; OS=overall survival; PFS=progression-free survival; RBC=red blood cell; TVE=thrombotic vascular eventa Note: Trial EPOANE4076 is being conducted by the Nephrology Society of Thailand and not by the MAH.

VI.1.3. Summary of Postauthorisation Efficacy Development Plan

No efficacy trials were required postauthorisation.


221

VI.1.4. Summary Table of Risk Minimisation Measures

Safety Concern RoutineRisk Minimisation Measures


Important identified risks

Thrombotic vascular events The increased risk of TVEs is described in Sections 4.4 and 4.8 of the SmPC.

Patients with cancer being treated for CIA should be monitored closely to ensure that the lowest approved dose of ESA is used to provide adequate control of symptoms of anaemia. Haemoglobin values should not be allowed to rise above 12 g/dL (SmPC Sections 4.2 and 4.4).

Thrombosis prophylaxis for TVEs in high-risk patients is also recommended (SmPC Section 4.4) and EPREX is contraindicated in surgery patients who for any reason cannot receive anti-thrombotic prophylaxis (SmPC Section 4.3). The use of EPREX is also not recommended in perisurgery patients with a baseline HGB >13 g/dL (SmPC Section 4.4).

None

Pure red cell aplasia Intravenous administration should be used when possible. Where IV access is not readily available, EPREX may be administered subcutaneously (SmPC Section 4.2).

Physicians are advised of the incidence of PRCA and measures that can be taken to diagnose PRCA, as stated in Sections 4.4 and 4.8 of the SmPC. The use of EPREX is contraindicated in patients who develop PRCA following treatment with any ESA (SmPC Section 4.3).

None

Hypertension/hypertensive crisis

The use of EPREX is contraindicated in patients with uncontrolled hypertension (SmPC Section 4.3). Blood pressure should be closely monitored and controlled as necessary (SmPC Sections 4.4 and 4.8). EPREX should be used with caution in the presence of untreated, inadequately treated, or poorly controllable hypertension. It may be necessary to add or increase antihypertensive treatment. If blood pressure cannot be controlled, EPREX treatment should be discontinued (SmPC Section 4.4).

None


222

Important potential risks

Disease progression When used according to labelled guidance for correction of anaemia in the setting of CIA, there is no evidence that epoetin alfa has an adverse effect on disease progression. However, the data suggest that ESA treatment may increase mortality in patients with head and neck cancer and breast cancer when administered to a target HGB concentration of 12 to 14 g/dL (SmPC Section 4.4). Epoetin alfa should be discontinued in non-responding patients (SmPC Section 4.2).

None

Survival impact When used according to labelled guidance for correction of anaemia in the setting of CIA, there is no evidence that epoetin alfa has an adverse effect on survival. However, the data strongly suggest that epoetin alfa treatment increases the risk of death and serious cardiovascular eventswhen administered to a target HGB concentration >12 g/dL (SmPC Sections 4.4 and 5.1); therefore, the target HGB concentration of 12 g/dL should not to be exceeded (SmPC Section 4.4). Patients should be monitored closely to ensure that the lowest approved dose of ESA is used to provide adequate control of symptoms of anaemia. Guidelines for dose and frequency of dose adjustments should be followed (SmPC Section 4.2)

None

Congestive heart failure The target HGB should be up to 12 g/dL and should not be exceeded. Haemoglobin concentrations >12 g/dL may be associated with a higher risk of cardiovascular events in patients with CRF (SmPC Section 4.4).

None

CIA=chemotherapy-induced anaemia; CNS=central nervous system; CRF=chronic renal failure; ESA=erythropoiesis-stimulating agent; HGB=haemoglobin; IV=intravenous; PRCA=pure red cell aplasia; SmPC=Summary of Product Characteristics; TVE=thrombotic vascular event

VI.2. Elements for a Public Summary

EPREX belongs to a group of medicines called other antianemic preparations and is used to treat

low red blood cell counts in patients. EPREX is available as a solution to be injected into a vein

or under the skin.


223

VI.2.1. Overview of Disease Epidemiology

Red blood cells carry oxygen from the lungs to all parts of the body, giving it energy to function.

EPREX increases red blood cell production in patients whose kidneys don’t work properly, have

low red blood cell counts from cancer treatments or bone marrow disease, donate their own

blood before surgery, or are having hip or knee replacement surgery.

Poor kidney function is common in patients more than 65 years old, but also occurs in

younger adults and children, and is more common in women.

Cancer treatments and bone marrow disease can hurt the body’s ability to produce red

blood cells. This is most comment in adult and older patients.

The practice of donating one’s own blood before surgery is limited in Europe and varies

from country to country.

Patients having hip or knee replacement surgery are generally more than 60 years old.

VI.2.2. Summary of Treatment Benefits

EPREX helps the body produce red blood cells and is given as an injection into a blood vessel or

under the skin. The amount of drug, how often it’s given, and how long it’s used depend on the

condition being treated and the patient’s body weight, and are adjusted according to how well the

treatment is working for the patient.

Drugs used to treat cancer and bone marrow disease can harm the body’s ability to produce red

blood cells. In these patients, EPREX has been shown to increase red blood cell amounts to

normal levels.

Kidneys make an important hormone called erythropoietin that tells the body to make red blood

cells. Kidneys that aren’t working properly can’t make enough erythropoietin, which causes the

amount of red blood cells in the body to decrease. In patients with kidney problems, EPREX has

been shown to increase red blood cell amounts to normal levels.

EPREX is used before surgery to increase red blood cell numbers and decrease the number of

procedures needed to replace blood or portions of the blood lost during the surgical procedure.

EPREX has been effectively used in thousands of patients since it was first approved for use in

1988.

VI.2.3. Unknowns Relating to Treatment Benefits

Many patients of both sexes, and all races and ages have been treated with EPREX since the

1980s. Little information is available about the benefit of EPREX for anaemia associated with

other diseases such as blood cancers as EPREX has not been studied in these conditions.


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VI.2.4. Summary of Safety Concerns


Risk What is known Preventability

Blood clots

(thrombotic vascular events)

Blood clots may affect the patient’s blood vessels, which may lead to painful swelling of the legs, and rarely, very dangerous clumping of blood cells in the lungs (blood clots). Clumped blood cells in the blood vessels near the heart may lead to a stroke.

Medicines to stop the clumping of blood cells may be prescribed by a doctor.

Patients being treated with EPREX should be checked closely to make sure the lowest dose is used to adequately control the amount of protein in the blood that carries oxygen to all parts of the body(haemoglobin).

Patients should receive medicine to help prevent blood cell clumping. EPREX should not be used in surgery patients who cannot receive medicines to prevent blood cell clumping. EPREX also should not be used in surgical patients in whom the amount of protein inside red blood cells that carry oxygen (haemoglobin) is above normal.

Reduced or stopped red blood cell production

(pure red cell aplasia)

The reduction or absence of red blood cell production happens very rarely. It can stop EPREX from working and make the red blood cell count go even lower. EPREX should not be used in patients who develop this condition after being treated with any drug similar to EPREX.

EPREX should be given as an injection into a blood vesselaccording to the proper instructions.

High blood pressure

(hypertension/hypertensive crisis)

High blood pressure is a common side effect of EPREX, but it can be treated. Blood pressure should be closely checked and controlled as needed, because if it is not treated, it can cause serious problems such as heart attacks and strokes.

High blood pressure can be managed by frequently checking blood pressure and giving medicine to lower blood pressure, as needed.

EPREX should be used with caution in patients with poorly controlled high blood pressure and should not be used in patients with uncontrollable high blood pressure. If blood pressure cannot be controlled, EPREX treatment should be stopped.


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Risk What is known

Worsening of disease

(disease progression)

There is no evidence that EPREX may worsen a patient’s cancerwhen used according to the Package Leaflet. However, if it is useddifferently, some patients with cancer who are treated with EPREXmay be more likely to have their cancer worsen.

Increase in potential deaths

(survival impact)

There is no evidence that EPREX may cause an increase in the possibility of death when used according to the Package Leaflet. However, if it is used differently, some patients with cancer treated with EPREX may be at a higher risk of dying.

Heart failure

(congestive heart failure)

The protein in blood that carries oxygen (haemoglobin) must be maintained at the level stated in the Package Leaflet to lower the risk of heart failure in patients with kidneys that are not working properly.

Missing Information

Risk What is known

None Not applicable

VI.2.5 Summary of Additional Risk Minimisation Measures by Safety Concern

All medicines have an SmPC, which provides physicians, pharmacists, and other health care

professionals with details on how to use the medicine, the safety risks, and recommendations for

minimising them. An abbreviated version of this in lay language is provided in the form of the

Package Leaflet. The measures in these documents are known as routine risk minimisation

measures.

The SmPC and Package Leaflet for EPREX are available nationally from the Company that

makes EPREX.

The Company considers that the safety risks associated with this medicine can be managed with

the information in the SmPC and Package Leaflet, and therefore no special conditions or

restrictions for its safe and effective use (additional risk minimisation measures) have been

proposed.


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VI.2.6 Planned Postauthorisation Development Plan

List of Studies in Postauthorisation Development Plan

Study/activity (including study number) Objectives

Safety concerns/efficacy issue addressed


Date for submission of (interim and) final results

Trial EPO-ANE-3010 Estimate how often patients treated drugs to fight breast cancer receiving EPREX plus red blood cell transfusions versus red blood cell transfusions alone developed worsening of their disease or blood clots

Worsening of disease; blood clots, increased risk of death

Ongoing Report for final OS in 4Q 2017

OS=overall survival.

Studies Which are a Condition of the Marketing Authorisation

No trials are currently required as a condition of marketing authorisation.


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VI.2.7 Summary of Changes to the Risk Management Plan Over Time

Major Changes to the Risk Management Plan Over Time

Version Date Safety Concerns Comment

1.0 08 Dec 2004 Original version of RMP. Submitted with response to EU Pharmacovigilance Working Party: Risk Management Plan for Potential Risk of Tumour Growth Progression in Cancer Patients Treated With Epoetins.

2.0 08 Jul 2005 Erythropoietin Ab-mediated PRCA in patients with CRF was added as an Important Identified Risk.

New risk identified.

3.0 24 Sep 2010 Information on 3 trials that have been completed: Trials EPO-AKD-3001, EPO-AKD-3002,EPO-ANE-4008, and EPO-CKD-2002.

Trial completion.

Updated enrolment number for PRIMS.

Information on new ADR that will be added to the CCDS, but will not be added to the RMP.

Adverse drug reaction risks were identified but no new ones were considered as important for RMP purposes.

Conclusion from TrialEPO-ANE-4008 on TVEs was added.

Trial completion.

Update included number of cases of erythropoietin Ab-mediated PRCA in patients with CRF associated with EPREX in coated-stopper prefilled syringes containing PS-80 in countries where these cases originated.

Warning and precaution statement that was added to the product SmPC during this reporting interval for an unapproved patient population.

4.0 26 Oct 2011 Exclusion Criteria were included in this section per the EMA template.

New template.

Regulatory Actions Taken was updated to include worldwide actions taken due to safety issues.

Previously this was EU countries only.


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Major Changes to the Risk Management Plan Over Time

Version Date Safety Concerns Comment

5.0 Updated document for consistency with template.

New template.

Added proposed text for the MDS indication and updated other relevant sections of document with information from MDS studies.

New indication.

Updated information on completed trials: EPOANE4076.

Trial completion.

5.1 Added new important potential risks: seizures and hypersensitivity/anaphylaxis; updated important identified risk of “hypertension” to “hypertension/hypertensive crisis”

Updated document for consistency with the SmPC

5.2 Updated with data from CSR EPOANE3010 and additional subjects from the CSR EPOANE3021 extension. In addition, changed the frequency of immunogenicity reports from semiannual to annual.

Trial completion.

5.3 Risks of seizures and hypersensitivity/anaphylaxis were moved from important potential risks to important identified risks.

As requested by ANSM

5.4 Risks of seizures and hypersensitivity/anaphylaxis were removed

As requested by ANSM

Ab=antibody; ADR=adverse drug reaction; CCDS=Company Core Data Sheet; CRF=chronic renal failure; EMA=European Medicines Agency; EU=European Union; MDS=myelodysplastic syndrome; PRCA=pure red cell aplasia; PRIMS=Pharmacoepidemiology Registry EPO-ANE-4014 Prospective Immunogenicity Surveillance; PS-80=polysorbate-80; RMP=risk management plan; SmPC=Summary of Product Characteristics; TVE=thrombotic vascular event

SIGNATURES

Date Justification

Signed by Lau

14Jun2018, 11:36:09 AM, UTC Document Approval

LIST OF ANNEXES

ANNEX 1: EUDRAVIGILANCE INTERFACE ................................................. ANNEX 2: SMPC AND PACKAGE LEAFLET................................................ ANNEX 3: WORLDWIDE MARKETING AUTHORISATION STATUS BY

COUNTRY ..................................................................................... ANNEX 4: SYNOPSIS OF THE ONGOING AND COMPLETED CLINICAL

TRIAL PROGRAMME ................................................................... ANNEX 5: SYNOPSIS OF THE ONGOING AND COMPLETED

PHARMACOEPIDEMIOLOGICAL................................................ ANNEX 6: PROTOCOLS FOR PROPOSED AND ONGOING STUDIES IN

CATEGORIES 1-3 OF THE........................................................... ANNEX 7: SPECIFIC ADVERSE EVENT FOLLOW-UP FORMS .................. ANNEX 8: PROTOCOLS FOR PROPOSED AND ONGOING STUDIES IN

RMP PART IV................................................................................ ANNEX 9: SYNOPSIS OF NEWLY AVAILABLE STUDY REPORTS FOR

RMP PARTS III-IV ......................................................................... ANNEX 10: DETAILS OF PROPOSED ADDITIONAL RISK MINIMISATION

ACTIVITIES ................................................................................... ANNEX 11: MOCK UP OF PROPOSED ADDITIONAL RISK MINIMISATION

MEASURES................................................................................... ANNEX 12: OTHER SUPPORTING DATA (INCLUDING REFERENCED

MATERIAL)....................................................................................

231232

542

549

580

581747

748

749

750

751

752

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european union risk management plan (eu-rmp) …...completed clinical trial programme 14 may2018 5.3...

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